Selenium as complementary therapy in oncology

Transcription

1 Selenium as complementary therapy in oncology selenase In all phases of the treatment and care of oncological patients The optimal dosage for each therapy phase we are research

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3 3 Supporting overall therapy with selenase Treatment phase Dosing Product Dose Se / Unit Preventive care Selenium deficiency in cancer patients Prevention genetic predisposition Therapy µg selenium daily µg Se daily Dose adjustment for low selenium levels (see table, page 55) 500 1,000 µg selenium daily selenase 50 peroral selenase 50 AP selenase 100 µg peroral 50 µg 50 µg 100 µg Surgery Surgery-related lymphedema, ENT tumors 1000 µg Se 1 h pre-op 1000 µg Se intra-, postoperative selenase T pro injectione 20 ml 1000 µg Secondary lymphedema µg Se daily (dose adjustment) selenase T pro injectione 10 ml selenase T pro injectione 20 ml selenase T peroral 500 µg 1000 µg 500 µg Chemotherapy Radiotherapy Aftercare 1000 µg Se 1 h before giving cytostatics 500 µg Se on therapy-free days 1000 µg Se 1 h before irradiation 500 µg Se on therapy-free days 300 µg selenium daily selenase T pro injectione 20 ml 1000 µg selenase T pro injectione 10 ml 500 µg selenase T peroral 500 µg selenase T pro injectione 20 ml 1000 µg selenase T pro injectione 10 ml 500 µg selenase T peroral 500 µg Aftercare 300 µg Se daily (dose adjustment) selenase 100 µg peroral selenase 300 RP 100 µg 300 µg It makes sense to measure selenium levels at regular intervals, as a prerequisite for proper dosing as well as if there is any reimbursement by the health insurance companies Tablets Drinking ampoule / drinking bottle Solution for injection

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5 Contents 5 Preventive care 6 Selenium deficiency in cancer patients 12 Prevention for genetic predisposition Therapy 16 Surgery 19 Surgery-related lymphedema 24 Secondary lymphedema 26 Chemotherapy 32 Radiotherapy Aftercare 38 Recurrences, quality of life and the immune system Additional information 44 General evidence on selenium 56 Sodium selenite as active ingredient 58 Overview of studies and references 74 biosyn Arzneimittel GmbH

6 6 Preventive care Selenium deficiency in cancer patients A low selenium status worsens prognosis selenase 50 peroral 50 µg / drinking ampoule Dosing µg Se daily selenase 50 AP 50 µg / tablet selenase 100 µg peroral 100 µg / drinking ampoule Cancer patients frequently suffer from low selenium levels A selenium deficiency is associated with a worse disease prognosis An inadequate selenium supply in healthy persons raises the cancer risk Prior to selenium therapy, a selenium assay should be conducted The German reference range for serum selenium concentrations is µg/l (equivalent to µg/l in whole blood) Selenium levels are often low in cancer patients Cancer patients frequently suffer from a disease-related selenium deficiency. A presumed reason for this is that the body has an elevated need for selenium, for instance, to maintain selenium-dependent immune system functions and protect against oxidative stress. Depleted selenium levels occur in patients various tumor localizations (Figure 1) [1 4]. Hence, it is not rare for cancer patients to be selenium deficient. In their study conducted in 2011, Stevens et al. investigated the selenium levels of 430 patients with hematological malignancies [5]. The authors observed a pronounced selenium deficiency in 45% of patients. This can also affect the prognosis in those afflicted.

7 Preventive care 7 Fig. 1 Serum selenium concentrations in oncological patients Average serum selenium concentration [µg/l] Breast cancer Case Control Case Control Case Control Case Control Case Control Lung cancer Laryngeal cancer Prostate cancer* Liver cancer * The serum levels for this indication were calculated from the whole blood levels documented in the study. Case n Control Source Breast cancer Lung cancer Laryngeal cancer Prostate cancer Liver cancer

8 8 Preventive care Low selenium levels worsen the prognosis According to Stevens et al., patients with verified selenium deficiency tended to have worse outcomes than patients with a higher selenium status [5]. One year later, a study on the prognostic value of selenium levels prognosis in renal cell cancer patients substantiated the above findings [6]. Survival in the affected patients declined as a function of lower serum concentrations of selenoprotein P (a reliable marker for selenium concentration) (Figure 2). Using this marker, the authors of the publication proved a correlation between the severity of selenium deficiency and overall survival in their patients. Selenium deficiency increases cancer risk in healthy persons Healthy persons can also suffer from a deficient supply of selenium, which elevates the risk of developing cancer. Back as early as the Seventies, the American scientist Gerhard Schrauzer postulated a correlations between low selenium levels and an elevated incidence of cancer [7]. Since then, innumerable epidemiological studies have underscored this evidence [8 11]. And finally, the Nutritional Prevention of Cancer (NPC) Trial investigated whether a nutritional supplement of selenium can decrease the incidence of cancer [12]. The 1,312 subjects received daily doses of 200 µg selenium as selenium-enriched yeast over a period of 4.5 years. The study end points were the incidence of nonmela noma carcinomas of the skin (primary end point) and of other cancers (secondary end point). Whereas no difference was found relating to the incidence of skin cancer, the selenium group overall had a significantly lower cancer incidence (all localizations) and, specifically, a lower hazard ratio for prostate cancer. This was also confirmed by a later subgroup analysis of the data on the 1,250 participants (Table 1) which accounted for a longer follow-up period of 12 years [13].

9 Preventive care 9 Fig. 2 Kaplan-Meier analysis of over survival in patients with renal cell cancer (n = 41) as a function of selenoprotein P serum concentration (SePP; biomarker for selenium concentration). Modified after [6]. 1.0 Highest tertile serum concentration SePP Proportion of survivors Middle tertile serum concentration SePP Bottom tertile serum concentration SePP 0 p = Months Tab. 1 Effect of selenium on cancer risk (modified after [13]) Cancer localization N= (selenium group) N= (placebo group) Hazard ratio (95% confidence interval) P value All localizations Prostate ( ) 0.48 ( )

10 10 Preventive care The Linxian trial followed nearly 30,000 patients; after ten years there were still beneficial effects detectable The benefit of preventive administration of selenium for reducing cancer risk was also demonstrated by another large-scale double-blind randomized trial conducted on the inhabitants of Linxian communes in Henan Province, China. This region has one of the highest rates of esophageal and gastric cancer in the world and nutritional deficiencies occur there with a common frequency. In the General Population Nutrition Intervention Trial, a total of 29,584 study participants aged 40 to 69 years received daily doses of four different combinations of vitamins and minerals over a period of 5 years [14]. The combination of selenium, vitamin E and beta-carotene (factor D) proved to decrease all-cause and cancer mortality. It was also associated with a lower rate of gastric cancer. The beneficial effects of this combination were event evident 10 years after the trial was completed. Overall mortality in 10-year follow-up was reduced by 5% in study participants who received the selenium, vitamin E and beta-carotene supplementation. In addition, 10 years after supplementation, a trend towards a lower rate of cancer-related deaths was observed HR 0.95 ( ) (Table 2). Interestingly, these effects were the greatest in participants younger than 55 years of age (Table 3). Selenium assays give confidence Before giving any preventive or adjuvant selenium supplementation, the patient's selenium status should be measured. The German reference range for selenium serum concentrations is µg/l (equivalent to µg/l in whole blood) [15]. Concentrations below this reference range are to be classified as deficient. If a selenium deficiency is diagnosed, the health insurance companies will reimburse the costs for supplementation. In this regard, a selenium deficiency can be detected earlier by measuring selenium levels in the whole blood than in the serum. Tab. 2 Hazard ratios for supplementation with selenium, vitamin E and beta-carotene vs. placebo after the five-year trial period and the ten year follow-up period (modified after [14]) Total mortality (factor D vs. no factor D) Cancer mortality (factor D vs. no factor D) * p < 0.05 after 5 years (duration of intervention study from ) after 15 years (duration of intervention study + 10-year follow-up from ) HR 0.91 ( ) HR 0.95 ( ) HR 0.91 ( ) HR 0.95 ( )

11 Preventive care 11 Tab. 3 Hazard ratios for total and cancer-specific mortality by age group ten years after supplementation with selenium, vitamin E and beta-carotene (modified after [14]) Total mortality (factor D vs. no factor D) Cancer mortality (factor D vs. no factor D) < 55 years at randomization, HR (95% CI) 55 years at randomization, HR (95% CI) p-value (difference between age groups) 0.88 ( ) 0.98 ( ) ( ) 1.02 ( ) References Charalabopoulos K, Kotsalos A, Batistatou A et al. Selenium in serum and neoplastic tissue in breast cancer: correlation with CEA. Br J Cancer 2006; 95: Jaworska K, Gupta S, Durda K et al. A low selenium level is associated with lung and laryngeal cancers. PLoS One 2013; 8: e Mücke R, Klotz T, Giedl J et al. Whole blood selenium levels (WBSL) in patients with prostate cancer (PC), benign prostatic hyperplasia (BPH) and healthy male inhabitants (HMI) and prostatic tissue selenium levels (PTSL) in patients with PC and BPH. Acta Oncol 2009; 48: Kazi TG, Kolachi NF, Afridi HI et al. Effects of mineral supplementation on liver cirrhotic/cancer male patients. Biol Trace Elem Res 2012; 150: Stevens J, Waters R, Sieniawska C et al. Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies. Br J Haematol 2011; 154: Meyer HA, Endermann T, Stephan C et al. Selenoprotein P status correlates to cancer-specific mortality in renal cancer patients. PLoS One 2012; 7: e Schrauzer GN, White DA, Schneider CJ. Cancer mortality correlation studies--iii: statistical associations with dietary selenium intakes. Bioinorg Chem 1977; 7: Bleys J, Navas-Acien A, Guallar E. Serum selenium levels and all-cause, cancer, and cardiovascular mortality among US adults. Arch Intern Med 2008; 168: Brooks JD, Metter EJ, Chan DW et al. Plasma selenium level before diagnosis and the risk of prostate cancer development. J Urol 2001; 166: van den Brandt PA, Zeegers MPA, Bode P et al. Toenail selenium levels and the subsequent risk of prostate cancer: a prospective cohort study. Cancer Epidemiol Biomarkers Prev 2003; 12: Babaknejad N, Sayehmiri F, Sayehmiri K et al. The relationship between selenium levels and breast cancer: a systematic review and meta-analysis. Biol Trace Elem Res 2014; 159: 1 7. Clark LC, Combs GF, Jr., Turnbull BW et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996; 276: Duffield-Lillico AJ, Reid ME, Turnbull BW et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev 2002; 11: Qiao YL, Dawsey SM, Kamangar F et al. Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. J Natl Cancer Inst. 2009; 101: Prescribing information selenase ; status March 2013.

12 12 Preventive care Prevention for genetic predisposition Selenium protects against DNA damage and enhances DNA repair capacity selenase 50 peroral 50 µg / drinking ampoule Dosing µg Se daily selenase 50 AP 50 µg / tablet selenase 100 µg peroral 100 µg / drinking ampoule In patients with a genetic predisposition, preventive interventions for lowering cancer risk are of paramount importance BRCA gene mutations diminish DNA damage repair capacity Selenium is an ROS scavenger and thereby reduce oxidative DNA damage Selenium promotes DNA repair capacity Selenium reduces oxidative DNA damage caused by BRCA-1 mutations in high-risk cancer patients Genetic predisposition an inalterable risk factor The pathogenesis of malignant diseases represents a complex interplay between exogenous and endogenous factors. Whereas external carcinogens (e.g., cigarette smoke) can be limited by abstention, a genetic predisposition to cancerous diseases remains inalterably anchored in a person's DNA. That is why preventive interventions are so very important for those affected and selenium possess special potential in this regard. BRCA mutations diminish DNA repair capacity There are numerous genotype variants that represent a predisposition for malignant diseases. Well-known examples include germ line mutations in the breast cancer gene (BRCA) 1 and 2. They code for proteins involved in DNA repair [1, 2]. If there is a mutation in the BRCA genes, the capacity to repair DNA damage is diminished and consquently the risk for cancer is higher: Women with mutations in one of these two genes, for instance, have a lifelong risk of 50 to 80% for developing breast cancer and 10 to 40% of developing ovarian cancer [3].

13 Preventive care 13 Selenium protects against DNA damage and promotes its repair Via an increased protein biosynthesis of selenium-dependent enzymes (e.g., glutathione peroxidases), selenium can promote the scavenging for reactive oxidative species (ROS) and thereby reduce oxidative stress [1]. Consequently, there is less damage to the DNA molecule and the risk for malignant neoplastic growth drops. Indeed, selenium not only prevents oxidative damage but promotes its repair as well: As myriad studies have shown, selenium enhances DNA repair capacity via glutathione peroxidase 1 (GPX-1) and the selenium-dependent thioredoxin reductase (TrxR). These two enzymes in turn influence repair enzymes and transcription factors like Gadd45 (Gadd = growth arrest and DNA damage), Ref-1 (Redox factor 1), p53 (Protein 53) and intact BRCA-1 (Figure 1) [1]. Fig. 1 Potential pathways via which selenium can protect against oxidative DNA damage and promote its repair (modified after [1]) Selenium Selenoprotein synthesis (GPX, TrxR) Glutathione peroxidase (GPx) Thioredoxin reductase (TrxR)??? Post-translational modifications ROS Gadd45 Ref1 BRCA1 Glycosylase activity p53 DNA damage DNA repair capacity Upregulation Downregulation Activation

14 14 Preventive care Selenium compensates DNA repair capacity in BRCA-1 mutations Dziaman et al. investigated the effect of selenium on oxidative DNA damage specifically in women carriers of BRCA-1 mutations whose DNA repair capacity was diminished [4]. As biomarkers of oxidative DNA damage, the authors measured 8-oxo-7,8-dihydro-2 -deoxyguanosine (8-oxodG) levels in leukocytes DNA [4]. Compared with healthy subjects, women with BRCA-1 mutations had a higher proportion of oxidative damage in leukocytes DNA [4]. Figure 2 illustrates that this effect was less pronounced on selenium supplementation as compared with placebo [4]. A similar study showed that the frequency of chromosome breaks was reduced in BRCA-1 mutation carriers receiving selenium supplementation [5]. Thus, selenium has the potential to protect DNA against carcinogenic damage and changes even when endogenous DNA repair capacity is diminished due to a genetic predisposition. Fig. 2 Median 8-oxodG levels in leukocytes DNA as biomarkers for oxidative DNA damage 8-oxodG/10 6 dg Cont. A 0 Plac. C 0 Se C 1 A 0 = Healthy women without BRCA-1 mutation (n = 91) C 0 = Breast cancer/ ovarian cancer patients with BRCA-1 mutation receiving placebo (n = 38) C 1 = Breast cancer/ ovarian cancer patients with BRCA-1 mutation receiving selenium (n = 16) (modified after [4]) Square = median, interval = 25 75% References 1 Bera S, De Rosa V, Rachidi W et al. Does a role for selenium in DNA damage repair explain apparent controversies in its use in chemoprevention? Mutagenesis 2013; 28: Hiddemann W, Bartram CR. Die Onkologie Teil 1. Springer Medizin Verlag, Heidelberg Guideline Program in Oncology of the AWMF (Association of the Scientific Medical Societies of Germany), the German Cancer Society (Deutsche Krebsgesellschaft e.v.) and German Cancer Aid (Deutsche Krebshilfe e.v.). GoR level III "Guidelines for the diagnosis, treatment and follow-up care of breast cancer". AWMF Register no OL (status: 2 July 2012). Dziaman T, Huzarski T, Gackowski D et al. Selenium supplementation reduced oxidative DNA damage in adnexectomized BRCA1 mutations carriers. Cancer Epidemiol Biomarkers Prev 2009; 18: Kowalska E, Narod SA, Huzarski T et al. Increased rates of chromosome breakage in BRCA1 carriers are normalized by oral selenium supplementation. Cancer Epidemiol Biomarkers Prev 2005; 14:

15 Preventive care 15 Preventive drugs as drinking ampoules or tablets Pharmacy only selenase 50 peroral selenase 50 AP 50 µg selenium per drinking ampoule 50 µg selenium per tablet 50 drinking ampoules with 1 ml oral solution (N2) Original packaging with 20 (N1), 50 (N2) and 100 (N3) tablets Prescription only selenase 100 µg peroral selenase RP Tabletten 100 µg selenium per drinking ampoule 79 µg Selen / tablet 20 (N1), 60 (N2), 90 or 100 (N3) drinking ampoules of 2 ml solution 50 (N2), or 100 (N3) tablets

16 16 Therapy Surgery Selenium reduced surgery-induced oxidative stress Dosing 1000 µg Se 1 h before surgery 1000 µg Se intra-, postoperative selenase T pro injectione 20 ml 1000 µg / injection Preoperative administration of selenium eliminated perioperative selenium deficiency Selenium reduced surgery-induced immune cell damage Postoperative immune deficiency Many cancer patients must undergo one or several surgical interventions. Each surgery is associated with oxidative stress and the production of free radicals, which also compromise healthy cells like those of the immune system. In the early postoperative phase, there is a transient reduction in circulating lymphocytes. This appears to play an important role in the immunosuppression frequently observed after surgical interventions. Transient postoperative immunodeficiency can elevate the risk for complications such as local infections and sepsis [1]. An accelerated apoptotic loss of lymphocytes promoted by the increased production of reactive oxygen species appears to be of crucial importance in postoperative immunosuppression. In patients requiring elective surgery under general anesthesia, Delogu et al. investigated the frequency of apoptotic CD4+ and CD8+ cells in the blood. The measurements were taken a day before surgery as well as 24 and 96 hours after the intervention. 24 hours postoperative, a significantly higher Percentage of apoptotic cells was found; after 96 hours the values were back to within the normal range (Figure 1). In healthy controls, by contrast, the CD4+ and CD8+ levels remained constant. The authors point out that the clinical potential of antioxidative therapy should be evaluated for this setting [1].

17 Therapy 17 Fig. 1 Apoptotic loss of T lymphocytes is a cause for postoperative immune deficiency day pre-op 24 h post-op 96 h post-op CD4+ CD8+ CD4+ CD8+ Surgery patients Controls Percentage of apoptotic CD4+ and CD8+ lymphocytes in surgery patients one day before, as well as 24 and 96 hours, after the surgical intervention. 24 hours after surgery, a significant increase in apoptotic lymphocytes was observed; after 96 hours these values had returned to the normal range [1]. Selenium activates the cell's antioxidative protective systems The essential trace element selenium is a component of key antioxidative enzymes and protects the body against free oxygen radicals [2]. Cancer patients commonly exhibit low selenium levels. This is an intercurrent condition of the underlying malignant disease and negatively impacts the clinical course. Studies have proven that low selenium levels in cancer patients are often associated with a worse outcome [3, 4]. Conversely, a sufficient selenium supply can support the immune defense in fighting cancer cells [5]. References Delogu A, Moretti S, Famularo G et al. Mitochondrial perturbations and oxidant stress in lymphocytes from patients undergoing surgery and general anesthesia. Arch Surg 2001; 136: Rayman MP. Selenium and human health. Lancet 2012; 379: Stevens J, Waters R, Sieniawska C et al. Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies. Br J Haematol 2011; 154: Meyer HA, Endermann T, Stephan C et al. Selenoprotein P status correlates to cancer specific mortality in renal cancer patients. PLoS One 2012; 7: e Kiremidjian-Schumacher L, Roy M, Glickman R et al. Selenium and immunocompetence in patients with head and neck cancer. Biol Trace Elem Res 2000; 73: Winnefeld K, Dawczynski H, Schirrmeister W et al. Selenium in serum and whole blood in patients with surgical interventions. Biol Trace Elem Res 1995; 50:

18 18 Therapy Perioperative selenium supplementation fights oxidative stress reactions Winnefeld and colleagues studied patients requiring extensive surgery of the gastrointestinal tract (e.g., gastrectomy) followed by total parenteral nutrition (TPE) [6]. At the commencement of TPE, all patients had low selenium values. A proportion of the patients received selenium supplementation which normalized their selenium levels within 6 to 7 days. In comparison to this, the group without selenium supplementation showed significantly lower values (Figure 2). From this, the authors conclude that selenium supplementation before major surgical interventions followed by TPE clearly helps patients combat the increase in oxidative stress reactions [6]. Fig. 2 Time curve of selenium level after surgical intervention Serum Whole blood 1.5 Normal range Se in µmol/l Normal range 0 Op Op Postoperative day with selenium supplementation without selenium supplementation Patients after extensive gastrointestinal surgery and subsequent total parenteral nutrition (TPE). At the commencement of TPE, all patients had low selenium values. In the group receiving selenium supplementation, selenium levels normalized within of 6 to 7 days, whereas the low selenium values persisted in the non-supplemented group. The average selenium levels in whole blood as well as the normal ranges are depicted [6].

19 Therapy 19 Surgery-related lymphedema Selenium prevents inflammation µg Se 1 h pre-op 1000 µg Se intra-, postoperative selenase T pro injectione 20 ml 1000 µg / injection Dosing cancer patients develop frequently postoperative lymphedema selenium reduced inflammation tendency and severity of the lymphedema that developed Elevated postoperative lymphedema risk Patients who have to undergo cancer thera py not rarely develop lymphedema, particularly after surgery or radiotherapy [1]. Operative interventions can result in acute or chronic lymphedema. Risk factors for the development of postoperative lymphedema include radical lymphectomy as well as wound healing disorders associated with the therapy for various cancers [2]. Selenium alleviates symptoms of lymphedema Studies show that patients with malignant diseases of can benefit from a complementary selenium therapy because an adequate selenium supply reduced inflammation tendency and edema volume in lymphedema [3]. After combined surgical and radiotherapy or even after radiotherapy alone, patients with head-and-neck tumors frequently develop lymphedema. As part of a study, 36 cancer patients with lymphedema of the head-and-neck received selenium therapy for 4 to 6 weeks. In 75% of the patients, the symptoms improved. 20 patients were suffering from larynx edema; 13 of them managed to avoid a tracheotomy [4].

20 20 Therapy Measurable reduction in edema volume One study investigated whether selenium therapy can reduce postoperative lymphedema after surgery for squamous cell carcinoma in floor of the mouth or root of tongue. A total of 20 patients who had undergone this type of surgery, including bilateral neck dissection, took part in the study. To objectify the extent of lymphedema, the investigators established a measuring distance (Figure 1), for example the tragus-chin tip distance. Using a measuring tape, these distance were measured preoperatively and as well as shortly after the intervention as well as one or two weeks postoperative. On the day of surgery, 10 patients received three doses of 1000 µg selenium as well as 1000 µg of selenium daily during the first three postoperative weeks; the others received a placebo (NaCl). Compared to the placebo group, a significant reduction in lymphedema was observed in the active drug group (Figure 2). The authors conclude, that sodium selenite represents a suitable complementary therapy for surgery-induced lymphedema in patients with cancer of the floor of the mouth or root of tongue [5]. References 1 Warren AG, Brorson H, Borud LJ et al. Lymphedema: a comprehensive review. Ann Plast Surg 2007; 59: Földi E. Das postoperative Lymphödem. Phlebologie 2011; 40: Kasseroller R. Der Einsatz von Selen beim Lymphödem. Med Klin (Munich) 1997; 92 Suppl 3: Bruns F, Büntzel J, Mücke R et al. Selenium in the treatment of head and neck lymphedema. Med Princ Pract 2004; 13: Zimmermann T, Leonhardt H, Kersting S et al. Reduction of postoperative lymphedema after oral tumor surgery with sodium selenite. Biol Trace Elem Res 2005; 106:

21 Therapy 21 Fig. 1 Measuring distances for quantifying lymphedema [5] Tragus Nasal wing Corner of mouth Tip of chin Fig. 2 Decrease in edema volume in cancer of the floor of the mouth or root of tongue 12 % p = p = preoperative postoperative 1 week 2 weeks selenase placebo Changes in the tragus-chin tip distance as a measure of the decrease in edema volume after surgery of cancer of the floor of the mouth or root of tongue. Compared to the placebo group, there was a significant reduction in lymphedema in patients treated with selenium.

22 22 Therapy Selenium helps alleviate head-and-neck lymphedema Among the patients with lymphedema of the head-and-neck receiving a selenium dose of 500 µg/day for 4 6 weeks, the lymphedema symptoms were reduced (measured as a > 1 improvement in the Miller score) in 75% and for laryngeal edema in 65% of the cases the necessity for tracheotomy could be averted [4]. Moreover, all patients treated with sodium selenite reported that their quality of life improved and they did not develop any erysipelas throughout the entire treatment period (Table 1). Tab. 1 The effectiveness of selenium for lymphedema after head-and-neck tumors proven The action of sodium selenite in patients (n = 36) with secondary lymphedema of the head and neck after surgery and radiotherapy [4]. The Miller score evaluates the extent of lymphedema based on clinical observations, like skin discoloration, restriction of movement or by palpation. Patients with lymphedema in the head-and-neck region (500 µg Se for 4 weeks, 4 months after radiotherapy) Quality of life improved by 4.4 points in 100% No occurrence of erysipelas in 100% Miller score improved by > 1 points in 75%

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24 24 Therapy Secondary lymphedema Sodium selenite accelerates the resolution of lymphedema selenase T pro injectione 10 ml 500 µg / injection Dosing µg Se daily dose adjustment with selenase T pro injectione 20 ml 1000 µg / injection selenase T peroral 500 µg / drinking bottle As side effects of combined chemo- and radiotherapy, many cancer patients develop lymphedema and infections Sodium selenite: reduces the extent of (radiogenic) lymphedema accelerates reduction in lymphedema volume prevents erysipelas has an anti-sclerotic effect on connective tissue With selenium, less inflammation tendency and reduced edema volume As a result of combined cancer therapy, many afflicted patients develop lymphedema. Frequently, a bacterial infection manifesting as erysipelas will occur as one of the most severe complications of lymphedema. In advanced stages of lymphedema, a remodeling of the connective tissue takes place with fibrosis and sclerosis. In this context, reactive oxygen species (ROS) play an important role [1]. For example, patients suffering from chronic lymphedema have high levels of malondialdehyde (MDA) and 4-hydroxynonenal (HNE) markers for oxidative stress concurrently with lowered levels of the antioxidatively active glutathione (GSH) [2]. Thanks to their antioxidative and anti-inflammatory effects, selenium drugs markedly reduced the inflammation tendency and lymphedema volume [3]. Breast cancer patients, in whom lymphedema of the arms is frequently observed, can also benefit from therapy with sodium selenite [4]. A repeat selenium administration given to postmastectomy patients not only reduced edema volume, but moreover prevented the occurrence of dangerous erysipelas in each woman (Figure 1) [5, 6].

25 Therapy 25 Fig. 1a Selenium administration in oncological patients with erysipelas and lymphedema % % Erysipelas incidence Placebo selenase Erysipelas incidence and lymphedema volume in patients (n = 60) with surgically treated breast cancer after therapy with sodium selenite versus placebo [6]. Fig. 1b Selenium administration in oncological patients with erysipelas and lymphedema % % ,3 % Reduction in lymphedema volume (p < 0.01) Placebo selenase Statistically significant, markedly greater reduction in edema volume with selenium administration and combined physical decongestive therapy compared to physical decongestive therapy alone in 84 patients with different cancer types [3]. References 1 Beier A, Siems W, Brenke R, Grune T. Verstärkte Bildung freier Radikale beim chronischen Lymphödem. Lymphol. 1994; 18: Siems WG, Brenke R, Beier A, Grune T. Oxidative stress in chronic lymphoedema. Q J Med 2002; 95: Kasseroller R. Natriumselenit in der Therapie des chronischen Lymphödems. Der Allgemeinarzt 1995; 13: Micke O, Bruns F, Mucke R et al. Selenium in the treatment of radiation-associated secondary lymphedema. Int J Radiat Oncol Biol Phys 2003; 56: Kasseroller RG, Schrauzer GN. Treatment of secondary lymphedema of the arm with physical decongestive therapy and sodium selenite: a review. Am J Ther 2000; 7: Kasseroller R. Sodium selenite as prophylaxis against erysipelas in secondary lymphedema. Anticancer Res 1998; 18:

26 26 Therapy Chemotherapy Sodium selenite reduced adverse reactions to chemotherapy 1000 µg Se 1 h before giving cytostatics selenase T pro injectione 20 ml 1,000 µg / injection Dosing 500 µg Se on therapy-free days selenase T pro injectione 10 ml selenase T peroral 500 µg / injection 500 µg / drinking bottle Selenium maintains immune functions Selenium can protect internal organs during chemotherapy Selenium alleviates adverse reactions to chemotherapy Selenium can prevent the induction of cytostatics resistance Boosting the immune system Various studies have shown that cancer patients are commonly deficient in selenium [1, 2]. This should be eliminated because selenium is indispensible for optimal functioning of the immune system. It boosts the immune defense against cancer cells and infections as well [3, 4, 5]. How do patients undergoing chemotherapy benefit from selenium administration? Cancer regimens like the chemotherapy induce the increased production of free radicals, thereby leading to oxidative stress. This impairs healthy cells and can destroy cells of the immune system [6, 7]. Cancer patients who have to undergo chemotherapy benefit in multiple ways from a complementary treatment with selenium/ selenase. An adequate selenium supply: improves immune defense against cancer cells [3, 4, 5] reduces adverse reactions to chemotherapy [8, 9] protects internal organs like heart and kindeys [10] appears to counteract the resistance of cancer cells to cytostatics [11] enhances apoptosis of cancer cells [14]. Studies have shown that treatment with sodium selenite depletes cancer cells of the protective factor glutathione (Figure 1) while at the same time enhancing the apoptosis of cancer cells [11, 12, 14].

27 Therapy 27 Fig. 1 Glutathione in tumor cells Glutathione in cancer cells [nmol/10 6 ] Control Cisplatin alone Cisplatin + sodium selenite When sodium selenite is administered in addition to the cytostatic cisplatin, it deprives the cancer cells of the protective factor glutathione (modified after [11]). Alleviation of chemotherapy-induced adverse reactions A chemotherapy is commonly associated with debilitating adverse reactions that can be alleviated by supportive selenium therapy. In this context, one controlled trial found that the intake of 200 µg selenium daily in patients with ovarian cancer can reduce the occurrence of hair loss, flatulence, abdominal pain, weakness, malaise and loss of appetite during chemotherapy [8]. Complementary therapy with selenium among others markedly alleviated the arthralgia and mucosal dryness frequently observed during adjuvant hormone therapy for breast cancer [9].

28 28 Therapy Organ protection and reduced infection rates with selenium Chemotherapy with cisplatin causes kidney damage in up to 30 to 50% of cases [10]. In one double-blind randomized controlled trial, 122 cancer patients undergoing a cisplatin chemotherapy received either a single oral selenium dose (400 mcg) or placebo. Whereas 7 patients in the placebo group developed acute renal insufficiency, no cases of acute renal failure occurred in the active drug group [10] (Figure 2). Another study was conducted on patients receiving chemotherapy for non-hodgkin s lymphoma. A proportion of patients were additionally treated with sodium selenite, which led to a significant reduction in neutrophil apoptosis (Figure 3). This was associated with a significant reduction in post-chemotherapy infection rates. Moreover, the authors observed a significant improvement in the cardiac ejection fraction in patients treated with sodium selenite [13]. Fig. 2 With selenium, there was no cisplatin-induced acute renal failure Cancer patients with various tumor entities on cisplatin therapy. With adjuvant selenium, no cases of cisplatin-induced acute renal failure occurred (modified after [10]). Proportion of patients with acute renal failure 12 % 0 % Placebo: 12 % Selenium: 0 %

29 Therapy 29 Fig. 3 Selenium improved outcome in patients with non-hodgkin s lymphoma Patients with non-hodgkin s lymphoma undergoing chemotherapy. The adjuvant administration of sodium selenite led to a significant reduction in neutrophil apoptosis as well as in postchemotherapy infection rates. Moreover, the selenite group experienced a significant improvement in cardiac ejection fraction (modified after [13]). % % -50 % Reduction in neutrophil apoptosis Day 8 vs. Day 0 67 % 20 % 64 % 62 % 63 % 69 % Placebo Selen Infection rate Initial Follow-up kardiale Cardiac ejection fraction

30 30 Therapy Protection against cytostatics resistance When chemotherapy fails, the reason is usually that the cancer cells have developed a resistance to the cytostatics, particularly in ovarian cancer [11]. Within an vivo system with human ovarian tumor cells, Caffrey et al. were able to demonstrate that administration of selenite or selenomethionine close to the time of the initial cisplatin dosing prevented drug resistance. Studies on tumor cell lines have demonstrated that selenium compounds prevent the induction of resistance by preventing a cisplatin-induced increase in glutathione levels [11]. Case reports Use of sodium selenite in complementary cancer therapy for advanced pancreatic cancer The currently 66-year-old patient lives on the Azorean island of Graciosa and receives his oncological treatment in both Germany and in his place of residence. With kind permission of Dr. P. Holzhauer, Bad Trissl 11/2011 Diagnosis of advanced, metastatic pancreatic cancer 12/2011 Induction of a holistic/complementary therapy Chemotherapy with gemcitabine/erlotinib Permanent optimization of selenium levels to µg/l Permanent optimization of vitamin D3 levels ng/ml 4 g carnitine pro day 3 3 g curcumin pro day 450 mg quercetin per day 2/2012 Moderate reduction in lung metastasis size 6/2012 Drop in the tumor marker CA 19-9 from initially 675 U/ml to 52.6 U/ml 6/2013 Progression of lung metastases, therefore chemotherapy was switched to 5-fluorouracil and oxaliplatin 2014 Patient with very good general status, no tumor progression

31 Therapy 31 References Navarro-Alarcón M, López-Martinez MC. Essentiality of selenium in the human body: relationship with the different diseases. Sci Total Environ 2000; 249: Rostkowska-Nadolska B, Pospiech L, Bochnia M. Content of trace elements in serum of patients with carcinoma of the larynx. Arch Immunol Ther Exp (Warsz) 1999; 47: Roy M, Kiremidjian-Schumacher L, Wishe HI et al. Supplementation with selenium and human immune cell functions. I. Effect on lymphocyte proliferation and interleukin 2 receptor expression. Biol Trace Elem Res 1994; 41: Kiremidjian-Schumacher L, Roy M, Glickman R et al. Selenium and immunocompetence in patients with head and neck cancer. Biol Trace Elem Res 2000; 73: McKenzie RC, Arthur JR, Beckett GJ. Selenium and the regulation of cell signaling, growth, and survival: molecular and mechanistic aspects. Antioxid Redox Signal 2002; 4: Look MP, Musch E. Lipid peroxides in the polychemotherapy of cancer patients. Chemotherapy 1994; 40: Conklin KA: Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr Cancer Ther 2004; 3: Sieja K, Talerczyk M. Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy. Gynecol Oncol 2004; 93: Beuth J, van Leendert R, Schneider B et al. Complementary medicine on side-effects of adjuvant hormone therapy in patients with breast cancer. In Vivo 2013; 27: Ghorbani A, Omidvar B, Parsi A. Protective effect of selenium on cisplatin induced nephrotoxicity: A double-blind controlled randomized clinical trial. Br J Haematol 2013; 2: Caffrey PB, Frenkel GD. Selenium compounds prevent the induction of drug resistance by cisplatin in human ovarian tumor xenografts in vivo. Cancer Chemother Pharmacol 2000; 46: Lanfear J, Fleming J, Wu L et al. The selenium metabolite selenodiglutathione induces p53 and apoptosis: relevance to the chemopreventive effects of selenium? Carcinogenesis 1994; 15: Asfour IA, El Shazly S, Fayek MH et al. Effect of high-dose sodium selenite therapy on polymorphonuclear leukocyte apoptosis in Non-Hodgkin s lymphoma patients. Biol Trace Elem Res 2006; 110: Wallenberg M, Misra S, Björnstedt M. Selenium cytotoxicity in cancer. Basic Clin Pharmacol Toxicol 2014; 114:

32 32 Therapy Radiotherapy Selenium reduced the adverse reactions of radiotherapy 1000 µg Se 1 h before irradiation selenase T pro injectione 20 ml 1,000 µg / injection Dosing 500 µg Se on therapy-free days selenase T pro injectione 10 ml selenase T peroral 500 µg / injection 500 µg / drinking bottle Selenium protects healthy cells against radiotherapy-induced damage and sensitizes cancer cells to the radiotherapy Selenium supplementation can reduce adverse reactions to radiotherapy The efficacy of radiotherapy is not impaired by selenium. The response to radiotherapy may even be potentiated Protecting healthy cells during radiotherapy The objective of radiotherapy is to damage cancer cells so intensely that they are destroyed. Despite great progress in the radiological treatment of cancer, damage to healthy cells and the resultant adverse reactions cannot be avoided entirely. Given its cytoprotective properties, selenium can help minimize the severity of adverse reactions. Selenium's mechanisms of action Selenium protects healthy cells against the negative sequelae of a radiotherapy various mechanisms of action: Selenium activates the immune system and thereby strengthens the entire body [1]. As a component of essential antioxidative enzymes like glutathione peroxidase, selenium protects the body against free oxygen radicals [1]. This mechanism of action is especially important in cancer therapy. That is because an increased number of reactive oxygen molecules are produced when cancer cells are destroyed during chemo- or radiotherapy. Selenium additionally supports the cellular mechanisms of DNA repair [2]. This way, selenium protects healthy cells against the genotoxic effects of radiotherapy.

33 Therapy 33 Fig. 1 Selenium protects healthy cells, sensitizes cancer cells to radiotherapy 1000 Survival fraction with (+) and without (-) selenase pretreatment Total radiation doses [Gy] Healthy cells Cancer cells + Se Se Se + Se modified after [7] Selenium sensitizes cancer cells to radiotherapy One special property of many cancer cells is that they contain extremely highly concentrations of glutathione [3]. This circumstance not only lends the cancer cells increased protection against oxidative stress, but can additionally promote the development of resistance to chemotherapeutic agents [4, 5]. Among others, selenium's cytotoxic action on cancer cells is based on the glutathione molecule's binding to selenodiglutathione [6]. Indeed, during this chemical reaction, harmful oxygen radicals are produced inside the cancer cell while at the same time it is depleted of protective glutathione [6]. This way, selenium or selenite help sensitize cancer cells to radiotherapy (Figure 1 [7]).

34 34 Therapy Fig. 2 Selenium plasma concentrations in breast cancer patients before and after radiotherapy µg/l p < % Reduction Before radiotherapy After radiotherapy Plasma selenium concentrations modified after [9] Fig. 3 Selenium reduces diarrhea Diarrhea in % % 20.5 % p = 0.04 Without selenase (n = 42) With selenase (n = 39) The incidence of CTC* grade 2 and higher diarrhea in patients with gynecological malignancies undergoing radiotherapy (modified after [10]). * Common Toxicity Criteria Selenium alleviates adverse reactions to radiotherapy An adequate selenium supply can boost immunity to cancer cells [8]. Cancer patients frequently have lower blood selenium concentrations which drop even further in many cases during radiotherapy (Figure 2) [9]. One of the sequelae is a diminished protection against oxidative stress because the activity of protective selenoenzymes like glutathione peroxidase also declines. Therefore, it makes sense to compensate for the selenium deficiency by complementing radiotherapy with selenium supplementation. In of one study, Mücke et al were able to demonstrate that serious adverse reactions of radiotherapy (e.g., diarrhea, see Figure 3) can be reduced by the cytoprotective properties of selenium [10].

35 Therapy 35 Fig. 4 Selenium does not impair the efficacy of cancer therapy with selenase without selenase p = months Overall survival in gynecological cancer patients over a period of 12 years. A proportion of the patients had received selenium supplementation during radiotherapy (modified after [11]). Important: The efficacy of radiotherapy remains unimpaired The use of cytoprotective substances to support radiotherapy in cancer patients begs the question as to whether the success of radiotherapy itself might be impaired by "protected" of cancer cells. During a follow-up period of 12 years, Mücke et al observed however that selenium does not impair therapy in terms of the patients' overall survival. In the selenium group, there was even a mild trend towards an improved overall survival evident (Figure 4) [11].

36 36 Therapy References 1 Rayman MP. Selenium and human health. Lancet 2012; 379: Bera S, De Rosa V, Rachidi W et al. Does a role for selenium in DNA damage repair explain apparent controversies in its use in chemoprevention? Mutagenesis 2013; 28: Estrela JM, Ortega A, Obrador E. Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci 2006; 43: Backos DS, Franklin CC, Reigan P. The role of glutathione in brain tumor drug resistance. Biochem Pharmacol 2012; 83: Kalinina EV, Berozov TT, Shtil AA et al. Expression of genes of glutathione transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 in tumor cells during the formation of drug resistance to cisplatin. Bull Exp Biol Med 2012; 154: Lanfear J, Fleming J, Wu L et al. The selenium metabolite selenodiglutathione induces p53 and apoptosis: relevance to the chemopreventive effects of selenium? Carcinogenesis 1994; 15: Hehr T, Bamberg M, Rodemann HP. Präklinische und klinische Relevanz der radioprotektiven Wirkung von Natriumselenit. InFoOnkologie 1999; 2 Suppl 2: Kiremidjian-Schumacher L, Roy M, Glickman R et al. Selenium and immunocompetence in patients with head and neck cancer. Biol Trace Elem Res 2000; 73: Franca CAS, Nogueira CR, Ramalho A et al. Serum levels of selenium in patients with breast cancer before and after treatment of external beam radiotherapy. Ann Oncol 2011; 22: Mücke R, Schomburg L, Glatzel M et al. Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. Int J Radiat Oncol Biol Phys 2010; 78: Mücke R, Micke O, Schomburg L et al. Multicenter, phase III trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization. Integr Cancer Ther [Epub ahead of print].

37 Therapy 37 Drugs for therapy supplied as injection solution, drinking ampoule, drinking bottle or tablet Prescription only selenase 100 µg peroral selenase T peroral selenase 300 RP 100 µg selenium per drinking ampoule 500 µg selenium per drinking ampoule 300 µg selenium per tablet 20 (N1), 60 (N2), 90 and 100 (N3) drinking ampoules of 2 ml solution Prescription only 10 ampoules each with 10 ml oral solution and 1 measuring cup 20 (N1), 50 (N2) und 100 (N3) tablets selenase 100 µg per injection selenase T pro injectione selenase T pro injectione 100 µg selenium per drinking ampoule 500 µg selenium per injection vial 1,000 µg selenium per injection vial 10 (N2) and 50 ampoules with 2 ml solution for injection 2, 10 (N2), 30 (3 10) and 50 (5 10) injection vials with 10 ml solution for injection 2, 10 (N2), 30 (3 10) and 50 (5 10) injection vials with 20 ml solution for injection

38 38 Aftercare Recurrences, quality of life and the immune system Selenium prevents recurrences, improves the quality of life and is essential for the immune system Dosing 300 µg selenium daily selenase 100 µg peroral 100 µg / drinking ampoule selenase 300 RP 300 µg / tablet Key aspects of cancer aftercare: Improve quality of life, detect recurrences early, implement interventions for preventing recurrences Immune defense cells can destroy cancer cells and thus mitigate the risk for recurrences Selenium can prevent recurrences by strengthening the immune system Selenium improves quality of life in cancer patients Improve quality of life and detect and prevent recurrences early Aftercare is an essential component in managing cancer patients. One of its main objectives is to alleviate the negative long-term sequelae of the disease or its treatment and help patients achieve the highest possible quality of life [1, 2]. On the other hand, follow-up examinations at close intervals (e.g. tumor marker assays), help detect recurrences early [1, 2]. In phase of follow-up care, attempts should moreover be made to actively counteract the development of recurrences or secondary tumors. These constitute interventions for risk factor reduction, like stop smoking programs or immunity-boosting therapies like selenium supplementation. The immune system fights cancer cells Among others, cytotoxic T-cells (Tc cells) are involved in the complex immune response to malignant cells. Mediate by features onthe tumor cell surface, they excrete cytokines like perforin and granulysin that are toxic to tissue and can induce the cell death (apoptosis) of the cancer cell [2]. If nevertheless cancer cells remain in the body after a cancer regimen with curative intent (e.g. multimodal combinations of R0 resection plus chemo- and radiotherapy), the immune system can destroy them and thereby prevent the growth of new tumor foci.

39 Aftercare 39

40 40 Aftercare Fig. 1 Selenium strengthens the immune system Responder in % CTL MLR PHA Under an eight-week selenium treatment, there was a larger proportion of responders with enhanced production of cytotoxic T-cells [cytotoxic T lymphocytes = CTL], increased lymphocyte reaction [mixed lymphocyte reaction = MLR] and enhanced responsiveness to phytohemagglutinin stimulation (PHA) (modified after [3]). Placebo Selenium selenium lowers the risk of recurrences by strengthening the immune system A study by Kiremidjian-Schumacher et al. determined that supplementation with selenium as sodium selenite given for cancer aftercare strengthens the patients' immunity and can achieve long-term positive effects. In this study, 33 patients with squamous cell carcinoma of the head and neck received 200 µg selenium or placebo daily over a period of eight weeks [3]. The result was an enhanced immune responsiveness on selenium also measured as an increased production of cytotoxic T-cells after 8 weeks (p < compared to baseline) (Figure 1) [3]. At the end of the study, a substantially enhanced lysis of cancer cells was observed (Figure 2) [3]. The study indicates that attacks on the cancer cells remaining in the body are better with concurrent selenium administration (Figure 3) and consquently these cells cannot develop into recurrences. The results of another study by Kiremedijan et al. support the assumption that selenium strengthens the body's endogenous mechanisms for fighting cancer cells. This preclinical study showed that tumor size in mice with interleukin-2-receptor-positive squamous cell carcinoma was reduced by 50% through the combination of selenium and peritumoral injections of IL-2. The size of early tumors even declined by 72.4% [4].

41 Aftercare 41 Fig. 2 Changes in the lysis of cancer cells Change in % weeks vs. baseline 8 weeks vs. 4 weeks 8 weeks vs. baseline Changes (in percent) in the ability of lymphocytes to differentiate into cytotoxic T-cells and destroy cells (lysis in percent) (modified after [3]). Placebo Selenium Fig. 3 Selenium enhances the ability of cytotoxic T-cells to destroy cancer cells of head-and-neck tumors by more than ten-fold Responders in % % Capability to destroy cancer cells 7.1 % Placebo (n = 16) 78.5 % NaSe (n = 17) (200 µg Se/d for 8 wk) modified after [3]

42 42 Aftercare Improved quality of life thanks to selenium Not just recurrence prophylaxis alone is important but cancer aftercare must especially focus on improving quality of life and maintaining it at the highest possible level [1, 2]. That selenium also confers benefits in regard was demonstrated in study conducted by Bruns et al. The quality of life was documented on an visual analog scale (VAS) by 36 patients with head-and-neck edema, 20 of whom had post-radiotherapy endolaryngeal lymphedema [5]. Patients receiving adjuvant selenium therapy rated their quality of life as markedly better than the comparator group on placebo [5]. Thus, thanks to its immunostimulating action and the improvement in the quality of life, selenium intake offers new opportunities for supporting cancer aftercare. References 1 German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). Aftercare in cancer. Online information from the DKFZ: (Stand: 23 August 2012). 2 Hiddemann W, Bartram CR. Die Onkologie Teil 1. Springer Medizin Verlag, Heidelberg Kiremidjian-Schumacher L, Roy M, Glickman R et al. Selenium and immunocompetence in patients with head and neck cancer. Biol Trace Elem Res 2000; 73: Kiremidjian-Schumacher L, Roy M. Effect of selenium on the immunocompetence of patients with head and neck cancer and on adoptive immunotherapy of early and established lesions. BioFactors 2001; 14: Bruns F, Büntzel J, Mücke R et al. Selenium in the treatment of head and neck lymphedema. Med Princ Pract 2004; 13:

43 Aftercare 43 Drugs for cancer aftercare supplied as drinking ampoule or tablet Prescription only selenase 100 µg peroral selenase 300 RP 100 µg selenium per drinking ampoule 300 µg selenium per tablet 20 (N1), 60 (N2), 90 or 100 (N3) drinking ampoules of 2 ml solution 20 (N1), 50 (N2), 100 (N3) tablets

44 44 Selenium General evidence on selenium Trace element with myriad anti-carcinogenic effects Selenium is a promising option in cancer therapy and prevention Selenium is an essential component of selenoenzymes that exert a variety of protective functions Selenium promotes the apoptosis of cancer cells and protects healthy cells Selenium acts as an immune activator/immunomodulator Selenium is a important component in DNA repair mechanisms An adequate selenium supply improves prognosis in cancer patients. Therefore, selenium should be supplemented in patient with an deficient supply Biological properties The essential trace element selenium possesses a number of biological properties that suggest its promising use in cancer prevention and therapy. Selenium is [1]: a radical scavenger per se, it binds and inactivates harmful free radicals an essential component of specific selenoenzymes (Table 1) an immune activator (which upregulates the IL-2 receptor, among others) an essential component of DNA repair and helps repair the damaged p53 tumor suppressor gene an anti-inflammatory agent (Figure 1) [4]. An abundance of research work done in the past years has demonstrated in various experimental models that selenium compounds inhibit the growth of malignant cells [2].

45 Selenium 45 Tab. 1 Selenium acts as an essential component of specific selenoenzymes Selenoproteins in mammals Frequency Importance Glutathione peroxidases Cytosol Plasma Cell membrane Gastrointestinal Thioredoxin reductases (TRxR) TRxRa: Cytosol TRxRb: Mitochondria Selenophosphate synthetase (SPS2) Iodothyronine deiodinase (ID) type I 5 ID, type II 5 ID, type III 5 ID Selenoprotein P (SeIP or SEPP1) Selenoprotein W Selenoprotein p15 In every cell High content: Thyroid function GI tract In every cell High content: Thyroid function In the whole body Plasma Liver and other tissue Brain Muscle Adrenal/thyroid gland prostate Protects cells against oxidant attack Reduces peroxides Protects endothelium Regulation of the redox status Participation in protein folding Endothelial protection DNA synthesis Regulation of cell cycle Selenoprotein biosynthesis activation of the thyroid hormone (deiodination of T4 to T3) Antioxidative function Transport of selenium or (HgSe)n

46 46 Selenium Fig. 1 Selenoenzymes regulate the activation of NF-κB Selenium deficiency has a pro-inflammatory effect Reactive oxygen radicals Activation Zytoplasm Nucleus NF-κB Binding to promoter gene Liver Selenoenzymes CRP GPx TNF-α IL-1 IL-6 Induction of pro-inflammatory cytokines Selenium has multiple mechanisms of anti-inflammatory action. The fact that the activity of the pro-inflammatory transcription factor NF-κB is downregulated is especially important. Free radicals and other signals trigger the release of NF-κB in the cytoplasm from the inactive precursor IκB, the transport of NF-κB into the cell nucleus where it induces binding to pro-inflammatory gene promoters. The resultant excretion of cytokines like TNF-α, IL-1 or IL-6 induces an inflammatory reaction.

47 Selenium 47 An adequate selenium supply inhibits inflammation Reactive oxygen radicals Zytoplasm Nucleus Neutralization Selenoenzymes Inhibition NF-κB No cytokines induction Liver Selenoenzymes CRP GPx Sufficiently high selenium levels enhance the synthesis and activity of selenoenzymes and thereby lead to free radical scavenging. That way, the entire signal cascade is never even set into motion. However, glutathione peroxidases can also extend the half-life of the inactive precursor IκB; less active NF-κB is produced and thus fewer pro-inflammatory cytokines are excreted. Obviously, genetic effects are important. For instance, gene polymorphisms are responsible for variations in the intensity of the inhibitory action of selenoprotein S on pro-inflammatory cytokines.

48 48 Selenium How does selenium act on cancer cells? One special property of many cancer cells is that they contain extremely highly concentrations of glutathione [5]. This circumstance not only lends the cancer cells increased protection against oxidative stress, but can additionally promote the development of a resistence to therapeutic agents by exporting them from the cancer cells [6, 7]. Among others, selenium's cytotoxic action on cancer cells is based on the glutathione molecule's binding to selenodiglutathione [8]. Indeed, during this chemical reaction, harmful oxygen radicals are produced inside the cancer cell while at the same time it is depleted of protective glutathione [8]. By contrast, no cytotoxic amounts of selenodiglutathione can collect in healthy cells due to the lower glutathione concentrations (Figure 2).

49 Selenium 49 Fig. 2 Mechanism of the cytotoxic action of selenium on cancer cells Cancer cells often have elevated glutathione concentrations Healthy cell Tumor cell Enhanced selenium inflow Glutathione Selenium Selenoglutathione Free oxygen radicals Mechanism of the cytotoxic action of selenium on cancer cells (modified after [5] and [8]). Due to the lower glutathione concentrations, no toxic concentrations of selenodiglutathione can collect in healthy cells.

50 50 Selenium Selenium activates the tumor suppressor gene p53 Moreover, selenium plays an important role in the regulation of tumor suppressor protein p53 [9, 10]. Thereby, selenium supports the functions of p53 in regulating the cell cycle and apoptosis. Over 50% of all tumor tissue carries a mutation or exhibits reduced expression of the p53 gene [11]. High-dose selenium therapy can enhance the expression of the p53 gene in cancer cells and in this way support primary therapy [2, 12]. Selenium protects healthy cells against the sequelae of cancer therapy Selenium protects healthy cells against the negative sequelae of a radiotherapy by various mechanisms of action: Selenium activates the immune system and thereby strengthens the entire body [1]. As a component of essential antioxidative enzymes like glutathione peroxidase, selenium protects the body against free oxygen radicals [1]. This mechanism of action is especially important in cancer therapy. That is because an increased number of reactive oxygen molecules are produced when cancer cells are destroyed during chemo- or radiotherapy. Selenium additionally supports the cellular mechanisms of DNA repair [13]. This way, selenium protects healthy cells against the genotoxic effects of radiotherapy. selenium is supportive in radio-oncological therapy A radiotherapy not only attackes cancer cells, but also healthy cells in the surrounding tissue. The administration of selenite protects healthy cells and sensitizes cancer cells to radiotherapy (Figure 3, 4). This reduces adverse reactions to radiotherapy [14].

51 Selenium 51 Fig. 3 Selenium protected healthy cells and sensitized cancer cells to radiotherapy (modified after [1] und [8]) Radiotherapy without selenium supplementation with selenium supplementation Healthy cells Blood vessel Tumor cells Blood vessel Irradiation not only attacks cancer cells, but the surrounding healthy cells as well. Cell damage moreover releases oxygen radicals which spread throughout the body. Healthy Cells Radiotherapy Blood vessel Tumor cells Blood vessel Selenium boosts the immune defense mechanisms of healthy cells, neutralizes free radicals and selectively sensitizes cancer cells to radiotherapy. Fig. 4 Selenium protects healthy cells, sensitizes cancer cells to radiotherapy modified after [19] Survival fraction with (+) and without (-) selenase pretreatment Total radiation doses [Gy] Healthy cells Cancer cells + Se Se Se + Se

52 52 Selenium After cancer therapy: Promoting regeneration of the immune system After cancer therapy, many patients have a weakened immune system. This state increases the risk of infection and also for tumor recurrences [15]. The aggressive therapy necessary in many tumors also tends to have a negative effect on the reconstitution of naive T-cells. That means that the body is lacking in exactly those cells that could mediate an immune response to new antigens like those from the tumor. Accordingly, regeneration of the immune system plays a key role in cancer aftercare and management. The importance of selenium in immunity To a large extent, immunity is modulated by interleukin-2 (IL-2). The secretion of IL-2 by T-helper cells triggers the activation and proliferation of other immune cell populations, particularly naive T cells. But in order to be able to exert this effect, IL-2 must be recognized by the corresponding receptors of the activating immune cell. In a resting naive T-cell, this receptor consists of two subunits (β and ɤ) and only exhibits low affinity for IL-2. The receptor attains its high affinity state by integration of a third subunit (α). Indeed, its expression is selenium-dependent (Figure 5) [18]. Fig. 5 Selenium activates immune responsiveness: the IL-2 receptor IL-2 Low-affinity IL-2R (K 0 ~10-9 M) β γ Resting naive T-cell β γ α Activated T-cell CD25 Se High-affinity IL-2R (K 0 ~10-11 M) An adequate selenium supply is prerequisite for the capacity of the high-affinity IL-2 receptor to do its work. In this way, selenium helps activate the immune response (modified after [3]).

53 Selenium 53 Summary and future perspectives Selenium possesses a myriad of antioxidative and immunomodulating properties [16]. As an essential constituent of selenoenzymes and selenocysteine-containing proteins, it helps protect cells against oxidative attacks and regulate the redox status. The anti-carcinogenic effects of selenium are based, among others, on the antiproliferative and pro-apoptotic action that trace elements exert on cancer cells [16]. Beyond this, additional properties like selenium-induced activation of the tumor suppressor gene p53 [2, 9, 12] and its boosting of humoral and cellular immunity [15, 16]. In one recent publication, Wallenberg et al. [2] pointed out selenium's great potential in oncology. Modern treatment options like targeted ligand-based strategies are specific for certain molecular targets. The agents are initial efficacious, but in many cases, the cancer cells rapidly develop a resistance to these drugs. By contrast, redox active selenium compounds like selenite in pharmacological concentrations induce complex signal transduction cascades that destroy cancer cells and exhibit a marked tumor specificity. In the view of the authors, these selenium compounds hold huge promise in multi-targeted chemotherapies [2]. An adequate selenium supply can improve prognosis in cancer patients. Therefore, the selenium levels of patients with malignant diseases should be checked regularly to determine whether they will benefit from selenium intake. Patients deficient in selenium should be supplemented until they reach a serum level of µg/l. Some authors even recommend up to 130 µg/l [17].

54 54 Selenium References 1 Rayman MP. Selenium and human health. Lancet 2012; 379: Wallenberg M, Misra S, Björnstedt M. Selenium Cytotoxicity in Cancer. Basic Clin Pharmacol Toxicol 2014; 114: Vollmar A, Dingermann T. Immunologie Grundlagen und Wirkstoffe. WVG, Stuttgart Duntas LH. Selenium and inflammation: underlying anti-inflammatory mechanisms. Horm Metab Res 2009; 41: Estrela JM, Ortega A, Obrador E. Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci 2006; 43: Backos DS, Franklin CC, Reigan P. The role of glutathione in brain tumor drug resistance. Biochem Pharmacol 2012; 83: Kalinina EV, Berozov TT, Shtil AA et al. Expression of genes of glutathione transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 in tumor cells during the formation of drug resistance to cisplatin. Bull Exp Biol Med 2012; 154: Lanfear J, Fleming J, Wu L et al. The selenium metabolite selenodiglutathione induces p53 and apoptosis: relevance to the chemopreventive effects of selenium? Carcinogenesis 1994; 15: Smith ML, Lancia JK, Mercer TI et al. Selenium compounds regulate p53 by common and distinctive mechanisms. Anticancer Res 2004; 24: Zeng H, Cheng WH, Johnson LK. Methylselenol, a selenium metabolite, modulates p53 pathway and inhibits the growth of colon cancer xenografts in Balb/c mice. J Nutr Biochem 2013; 24: Leroy B, Anderson M, Soussi T. TP53 mutations in human cancer: database reassessment and prospects for the next decade. Hum Mutat 2014; 35: Tsavachidou D, McDonnell TJ, Wen S et al. Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst 2009; 101: Bera S, De Rosa V, Rachidi W et al. Does a role for selenium in DNA damage repair explain apparent controversies in its use in chemoprevention? Mutagenesis 2013; 28: Mücke R, Schomburg L, Glatzel M et al. Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. Int J Radiat Oncol Biol Phys 2010; 78: Mitra DK, Singh HP, Singh M et al. Reconstitution of naive T cells and type 1 function after autologous peripheral stem cell transplantation: impact on the relapse of cancer. Transplantation 2002; 73: Gröber U. Mikronährstoffe. 3rd Ed. WVG, Stuttgart 2010 (S. 263ff) Gröber U, Mücke R, Adamietz IA et al. Komplementärer Einsatz von Antioxidanzien und Mikronährstoffen in der Onkologie. Der Onkologe 2013; 19: Kiremidjian-Schumacher L, Roy M, Glickman R et al. Selenium and immunocompetence in patients with head and neck cancer. Biol Trace Elem Res 2000; 73: Hehr T, Bamberg M, Rodemann HP. Präklinische und klinische Relevanz der radioprotektiven Wirkung von Natriumselenit. InFoOnkologie 1999; 2 Suppl 2:

55 Selenium 55 selenase by prescription for oncological patients Selenium levels Reference range* Whole blood Serum Status < 100 µg/l (< 1.3 µmol/l) < 80 µg/l (< 1.0 µmol/l) Lowered (below reference range) µg/l ( µmol/l) µg/l ( µmol/l) Low (within reference range) * No selenium need be administered at selenium levels > 140 µg/l in whole blood and 120 µg/l in serum. Reimbursement by healthcare insurance (after measuring selenium levels) Normal prescription The selenium level is low and below the reference range. If a selenium deficiency is clinically diagnosed, the health insurance companies will reimburse the costs for selenase. Over the counter Because the selenium level is still within the reference range, selenase will probably not be covered by the health insurance. Nevertheless, a variety of studies have concluded that selenium levels need to be raised into the upper reference range in order to improve the patient's status. * References available from biosyn

56 56 Sodium selenite Sodium selenite as active ingredient Why sodium selenite as the active ingredient? Why in the form of sodium selenite pentahydrate? The active ingredient of selenase is sodium selenite pentahydrate for a good reason! There are organic and inorganic selenium compounds. selenase contains sodium selenite pentahydrate as the active ingredient for a good reason: The advantageous property of sodium selenite pentahydrate is that, immediately after its entry into the body, the selenium from this salt is incorporated into specific, selenium-dependent enzymes or proteins and is not just stored in the body if in excess, but rather is rapidly excreted again. Moreover, it can directly detoxify oxygen radicals in the acidic environment without having to wait for enzyme biosynthesis of the corresponding glutathione peroxidases. Nutritional supplements often contain organic selenium-enriched yeast. In such products, selenium is mainly available as selenomethionine, which is closely related to the amino acid methionine. The sulfur atom of methionine is replaced by a selenium atom. After uptake, selenomethionine is initially incorporate non-specifically in the body's protein at those sites where the genetic code expects "methionine". This is because the protein synthesis machinery cannot precisely differentiate between "selenomethionine" and "methionine". In order to be incorporated into a specific selenium-dependent protein, such "organically bound" selenium must be converted via many metabolic pathways and is thus not directly bioavailable. Moreover, this non-specific incorporation can lead to an accumulation of selenium in the body which might have adverse effects. Hence, the inorganic form of selenium, sodium selenite, has better bioavailability and better tolerated. For this reason, only drugs with sodium sele nite pentahydrate as the active ingredient are approved and set down in the phar-

57 Sodium selenite 57 macopeial monographs. Since 2005, compliance with Good Manufacturing Practice (GMP) guidelines for manufacturing pharmaceuticals is legally prescribed for the production of pharmaceutical ingredients. Not only for that reason, biosyn has implemented a proprietary GMP-active ingredient production for sodium selenite pentahydrate and sodium selenite anhydrous: To date, this is the only one of its kind in the world. This innovative manufacturing process which yields pure sodium selenite pentahydrate crystals after ultra purification, has meanwhile been granted worldwide patents. In particular, the active ingredient obtained by GMP-compliant methods is used for the production of the selenase injection formulations sold worldwide. This process is also used to manufacture selenase drinking ampoules and selenase tablets as well as for the selenase food supplements. selenase eliminates selenium deficiency selenase : Active ingredient: Sodium selenite pentahydrate selenase 100 µg pro injectione, selenase T pro injectione, selenase 100 µg peroral, selenase T peroral, selenase 50 peroral: 50 µg selenium pro ml, selenase 50 AP: 50 µg selenium per tablet, selenase RP Tabletten: 79 µg selenium per tablet, selenase 300 RP: 300 µg selenium per tablet Therapeutic indications: selenase 100 µg pro injectione, selenase T pro injectione, selenase 100 µg peroral, selenase T peroral: Clinically proven selenium deficiency that cannot be compensated by nutritional sources. Selenium deficiency may be due to maldigestion, malabsorption, malnutrition and nutrient deficiencies (e.g. during total parenteral nutrition). selenase 50 peroral, selenase 50 AP, selenase RP Tabletten, selenase 300 RP: Clinically proven selenium deficiency that cannot be compensated by nutritional sources. Selenium deficiency may be due to maldigestion, malabsorption, malnutrition and nutrient deficiencies. Composition: selenase 100 µg pro injectione: 1 vial with 2 ml injection solution contains: mg sodium selenite pentahydrate, equivalent to 100 µg selenium. selenase T pro injectione: 1 injection vial with 10 ml / 20 ml solution for injection contains: 1.67 mg / 3.33 mg sodium selenite pentahydrate, equivalent to 500 µg / 1,000 µg (micrograms) selenium selenase 100 µg peroral: 1 drinking ampoule with 2 ml oral solution contains: mg sodium selenite pentahydrate, equivalent to 100 µg selenium. selenase T peroral: 1 ml solution contains: mg sodium selenite pentahydrate, equivalent to 50 µg selenium. selenase 50 peroral: 1 drinking ampoule with 1 ml solution contains 50 μg pure selenium in the form of sodium selenite pentahydrate in 0.9% NaCl solution. Excipients: Sodium chloride, hydrochloric acid, water for injections selenase 50 AP, selenase 300 RP: 1 tablet contains mg and mg sodium selenite pentahydrate (equivalent to 50 µg and 300 µg selenium). Excipients: Gelatin, magnesium stearate (Ph. Eur.), corn starch, sucrose, talcum. selenase RP Tabletten: 1 tablet contains 263 µg sodium selenite pentahydrate (equivalent to 1 µmol = 79 µg selenium). Excipients: Microcrystalline cellulose, sorbitol (Ph. Eur.), povidone K25, magnesium stearate (Ph.Eur.), stearic and palmitic acid. Contraindications: Selenosis. Undesirable Effects: None known, when used as directed. Pharmaceutical form, package size: selenase 100 µg pro injectione: 10 (N2) or 50 ampoules with 2 ml solution for injection. selenase T pro injectione: 2 or 10 (N2) injection vials with 10 ml solution for injection, hospital pack 30 (3 10) or 50 (5 10) injection vials with 10 ml solution for injection, 2 or 10 (N2) injection vials with 20 ml solution for injection, hospital pack 30 (3 10) or 50 (5 10) injection vials with 20 ml solution for injection. selenase 100 µg peroral: 20 (N1), 60 (N2), 90 or 100 (N3) drinking ampoules of 2 ml solution selenase T peroral: 10 drinking bottles each with 10 ml oral solution and 1 measuring cup. selenase 50 peroral: 50 drinking ampoules with 1 ml oral solution (N2) selenase 50 AP: 20 (N1), 50 (N2), 100 (N3) tablets selenase RP Tabletten: 50 (N2), 100 (N3) tablets. selenase 300 RP: 20 (N1), 50 (N2) and 100 (N3) tablets. selenase 100 µg pro injectione, selenase T pro injectione, selenase 100 µg peroral, selenase T peroral, selenase RP Tabletten, selenase 300 RP: Prescription only. selenase 50 peroral, selenase 50 AP: Subject to sale in pharmacies. 11/13

58 58 References Overview of studies and references Synopsis of the cited studies and references Asfour IA, El Shazly S, Fayek MH et al. Effect of high-dose sodium selenite therapy on polymorphonuclear leukocyte apoptosis in Non-Hodgkin s lymphoma patients. Biol Trace Elem Res 2006; 110: Babaknejad N, Sayehmiri F, Sayehmiri K et al. The relationship between selenium levels and breast cancer: a systematic review and meta-analysis. Biol Trace Elem Res 2014; 159: 1 7 Backos DS, Franklin CC, Reigan P. The role of glutathione in brain tumor drug resistance. Biochem Pharmacol 2012; 83: Beier A, Siems W, Brenke R, Grune T. Verstärkte Bildung freier Radikale beim chronischen Lymphödem. Lymphol. 1994; 18: 8 11 Sodium selenite dose (0.2 mg/kg/d) during chemotherapy (CHOP: cyclophosphamide, doxorubicin, oncovin, prednisone), given on day 3 7, respectively, reduced the adverse effects of chemotherapy: Significant reductions in neutrophil apoptosis (p < 0.05) and infection rate (p < 0.05) and improvement in cardiac ejection fraction (p < 0.05). Systematic review. Studies where selenium concentrations measured in the serum showed a significantly inverse correlation between selenium concentrations and the occurrence of breast cancer. In the studies where selenium was measured in the toenails, the correlation was not significant. The selenium concentration in blood can be used as a predictor for breast cancer. Many tumors exhibit a dysregulated GSH system, often manifesting as a tendency to cytostatic resistance. Usually, this is associated with a glutathione-s-transferase-mediated GSH conjugation of various anticancer agents, which in turn leads to the formation of less toxic GSH-cytostatic complexes that can be readily exported from the cell. Understanding of the mechanisms of cytostatic resistance and knowledge about the biomarker profile of the individual brain tumor patient are crucial for adapting therapeutic strategies and improving outcomes. In patients with lymphedema, the erythrocyte glutathione concentrations were around 20% lower than in healthy persons. Moreover, an increase in malondialdehyde concentrations in the serum was noted in these patients. These changes are evidence of a massive production and activity of free radicals present in lymphatic edematous tissue.

59 References 59 Bera S, De Rosa V, Rachidi W et al. Does a role for selenium in DNA damage repair explain apparent controversies in its use in chemoprevention? Mutagenesis 2013; 28: Beuth J, van Leendert R, Schneider B et al. Complementary medicine on side-effects of adjuvant hormone therapy in patients with breast cancer. In Vivo 2013; 27: Bleys J, Navas-Acien A, Guallar E. Serum selenium levels and all-cause, cancer, and cardiovascular mortality among US adults. Arch Intern Med 2008; 168: Sodium selenite reduced the risk for tumor growth by virtue of its ability to inhibit the development of DNA damage and promote its repair (radical scavenger per se, incorporated in selenoproteins, e.g., enhances Gadd45, Ref1, p53, protects BRCA1). 680 patients were treated according to international guidelines. All patients were suffering from arthralgia and mucosal dryness induced by the hormone therapy. To reduce their side-effects, the patients received complementary treatment with a combination of sodium selenite, proteolytic plant enzymes and Lens culinaris lectin. 64% and 62% of patients suffering from severe arthralgia and mucosal dryness, respectively, significantly benefited from the complementary treatment. The reduction in hormone therapy-related side-effects was statistically significant (p < 0.001). No linear connection between increasing selenium levels and the risk for diabetes type II higher mortality risk. In fact, the mortality risk drops proportionate to the rise in selenium levels (not until 150 µg/l in the serum does this risk increase) higher cancer mortality. In fact, the cancer mortality drops proportionate to the rise in selenium levels (not until 150 µg/l in the serum does this risk increase) For prostate and colon cancer the following even applies: the higher the selenium levels, the better the occurrence of chronic cardiovascular diseases. Increasing serum selenium levels up to approx. 130 µg/l are associated with declining mortality. This is above the upper German reference value of 120 µg/l Se in serum!

60 60 References Brooks JD, Metter EJ, Chan DW et al. Plasma selenium level before diagnosis and the risk of prostate cancer development. J Urol 2001; 166: Bruns F, Büntzel J, Mücke R et al. Selenium in the treatment of head and neck lymphedema. Med Princ Pract 2004; 13: Caffrey PB, Frenkel GD. Selenium compounds prevent the induction of drug resistance by cisplatin in human ovarian tumor xenografts in vivo. Cancer Chemother Pharmacol 2000; 46: Charalabopoulos K, Kotsalos A, Batistatou A et al. Selenium in serum and neoplastic tissue in breast cancer: correlation with CEA. Br J Cancer 2006; 95: men diagnosed with prostate cancer were compared to 96 age-matched controls with no detectable prostatic disease. Low plasma selenium levels were associated with a 4- to 5-fold increased risk of prostate cancer. Thus, supplementation may be particularly beneficial to older men since plasma selenium decreases with patient age. 20 patients with endolaryngeal lymphedema after surgery followed by radiotherapy received 350 μg Se/m 2 body surface/day for 4 6 weeks thereafter: 75% of the patients showed improvement in Miller score > 1 points and quality of life points (p > 0.05). In 65% of the patients, tracheostomy was not necessary. In 100% of the patients, no erysipelas. The administration of selenite or selenomethionine (i.p. 1.5 mg/kg) close to the time of the initial cisplatin dosing prevented drug resistance. The reason for this is that selenium compounds prevent a cisplatin-induced increase in protective glutathione. 80 mastectomized women with breast cancer. Serum selenium was 42.5 ± 7.5 µg/l in the breast cancer patients and 67.6 ± 5.36 µg/l in the age-matched healthy controls. An inverse correlation between selenium and CEA (carcinoembryonic antigen) was found in both groups (r = 0.794). There was no correlation between Se serum/tissue concentrations and disease stage. The drop in Se serum concentrations, just like increased concentrations in the tumor tissue, are of great importance. These changes may reflect some of the defense mechanisms against the neoplastic process.

61 References 61 Clark LC, Combs GF, Jr., Turnbull BW et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996; 276: Conklin KA. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr Cancer Ther 2004; 3: Delogu A, Moretti S, Famularo G et al. Mitochondrial perturbations and oxidant stress in lymphocytes from patients undergoing surgery and general anesthesia. Arch Surg 2001; 136: German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). Aftercare in cancer. Online information from the DKFZ: (Stand: 23 August 2012) Duffield-Lillico AJ, Reid ME, Turnbull BW et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev 2002; 11: Double-blind, placebo-controlled cancer prevention trial on 1,312 risk patients (treated for basal or squamous cell carcinomas of the skin). Trial on the effect of a 4.5-year Se supplementation (200 µg Se/day as Se Met) on cancer incidence: There was no effect on the recurrence rate, but on secondary end points: significant reduction in the incidence of prostate cancer (by 63%), colon cancer (by 58%), lung cancer (by 45%) and cancer mortality (16%). Antineoplastic agents given as part of chemotherapy to kill tumor cells also generates numerous electrophilic aldehydes that can impair the cell's metabolism to such an degree that diminishes the efficacy of chemotherapy. The use of anti-oxidants during chemotherapy might reduce the oxidative stress responsible for the generation of aldehydes. Surgeries can cause damage to the immune system; this can be demonstrated by the higher proportion of apoptotic lymphocytes (CD4, CD8) 24 h postoperative. The Cancer Information Service (KID) of the German Cancer Research Center (DKFZ) is your competent contact and liaison for all questions relating to the subject of cancer, both for laypersons and the medical community. Summary of the Nutritional Prevention of Cancer (NPC) trial of 1996 and analysis of its follow-up data. The NPC trial once more proved a carcinopreventive effect for selenium, although the incidence was not reduced in all cancer types. The treatment effect was restricted to men and those with low selenium levels.

62 62 References Duntas LH. Selenium and inflammation: underlying anti-inflammatory mechanisms. Horm Metab Res 2009; 41: Dziaman T, Huzarski T, Gackowski D et al. Selenium supplementation reduced oxidative DNA damage in adnexectomized BRCA1 mutations carriers. Cancer Epidemiol Biomarkers Prev 2009; 18: Estrela JM, Ortega A, Obrador E. Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci 2006; 43: Földi E. Das postoperative Lymphödem. Phlebologie 2011; 40: Franca CA, Nogueira CR, Ramalho A et al. Serum levels of selenium in patients with breast cancer before and after treatment of external beam radiotherapy. Ann Oncol 2011; 22: Ghorbani A, Omidvar B, Parsi A. Protective effect of selenium on cisplatin induced nephrotoxicity: A double-blind controlled randomized clinical trial. J Nephropathology 2013; 2: This review evaluates some key mechanisms of selenium relating to its anti-inflammatory properties (nuclear factor kappa-b (NF-kB) and advocates selenium as a modulator of inflammatory response in infectious and autoimmune disease. BRCA1 play a role in the repair of oxidative DNA damage. BRCA-1 mutation carriers (and thus with a substantially higher cancer risk) exhibited a marked elevation in oxidative DNA damage (determined by measuring 8-oxo-dG, i.e. oxidatively damaged guanosine nucleotides). Mutation carriers who had not yet contracted breast cancer subjected themselves to an adnexectomy and received selenium supplementation, had markedly less oxidative DNA damage. Hence, selenium supports DNA repair. Systematic review: Metabolic pathways of glutathione (GSH), responses to stress, molecular mechanisms of cancer cell survival and death, and sensitization of metastatic cells. Experimental data show that selective GSH depletion in metastatic cells is facilitated by the acceleration of GSH efflux from the cell. Review on postoperative lymphedema: Pathophysiology, diagnostics and therapy. Patients (n=209 with breast cancer) undergoing radiotherapy exhibited a significant reduction in plasma selenium levels: When radiotherapy began, the mean selenium value for all patients was 86.4 μg/l; after radiotherapy it had dropped to 47.8 μg/l. Statistically significant differences in the plasma selenium concentration before and after radiotherapy were shown for age, BMI, smoking, alcoholism, chemotherapy and clinical stage (p < each) by multivariate analysis. In 122 cancer patients (61/61) undergoing chemotherapy, The nephrotoxicity induced by cisplatin therapy was diminished by adding selenium 400 µg, one day before each chemotherapy session.

63 References 63 Gröber U, Mücke R, Adamietz IA et al. Komplementärer Einsatz von Antioxidanzien und Mikronährstoffen in der Onkologie. Der Onkologe 2013; 19: Gröber U. Mikronährstoffe. 3rd Ed. WVG, Stuttgart 2010 (S. 263ff) Hehr T, Bamberg M, Rodemann HP. Präklinische und klinische Relevanz der radioprotektiven Wirkung von Natriumselenit. InFoOnkologie 1999; 2 Suppl 2: Hiddemann W, Bartram CR. Die Onkologie Teil 1. Springer Medizin Verlag, Heidelberg 2010 Jaworska K, Gupta S, Durda K et al. A low selenium level is associated with lung and laryngeal cancers. PLoS One 2013; 8: e59051 Kalinina EV, Berozov TT, Shtil AA et al. Expression of genes of glutathione transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 in tumor cells during the formation of drug resistance to cisplatin. Bull Exp Biol Med 2012; 154: Kasseroller R. Der Einsatz von Selen beim Lymphödem. Med Klin (Munich) 1997; 92 Suppl 3: selenase 2013 Update by the working group on the complementary use of micronutrients in oncology with emphasis on vitamin D, selenium, L-carnitine and vitamin C. Chapter on the importance of micronutrients in cancers, including dose recommendations. In-vitro-studies on cell cultures of normal human fibroblasts and squamous cell carcinoma cell lines showed a selective radioprotection with selenite in that cell survival was improved for healthy cells as compared to cancer cells. Modern encyclopedia of clinical oncology. Vol. I: Solid clinical basics on the fundamental principles of therapy, epidemiology, etiology and pathogenesis. Case control study: lung cancer (n=95), lung and laryngeal cancer (n=113) and healthy controls. Selenium levels < 60 µg/l were associated with a significantly higher risk for lung and laryngeal cancers. The analysis of four selenoprotein genes revealed modest evidence of an association of genetic variant in GPX1 with the risk of lung and laryngeal cancers. Study of the expression of genes encoding glutathione-s-transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 that occur during the development of the resistance of human erythroleukemia (K562), mammary adenocarcinoma (MCF-7) and ovary adenocarcinoma (SKOV-3) cells to cisplatin (CDDP). In all three strains of tumor cells, the drug resistance that developed was associated with a significant increase in hgstp1 and hgsta4 gene expression. By contrast, elevated hgstk1 gene expression was only found in resistant K562/CDDP and MCF-7/CDDP cells. Review summarizing the beneficial effects of selenite in lymphedema : significant improvement in Walchsee index (skin dryness, depression, temperature sensitivity, incontinence, vision), continual volume reduction, softening of fibroses, complete resolution of erysipelas.

64 64 References Kasseroller R. Natriumselenit in der Therapie des chronischen Lymphödems. Der Allgemeinarzt 1995; 13: selenase Kasseroller R. Sodium selenite as prophylaxis against erysipelas in secondary lymphedema. Anticancer Res 1998; 18: selenase Kasseroller RG, Schrauzer GN. Treatment of secondary lymphedema of the arm with physical decongestive therapy and sodium selenite: a review. Am J Ther 2000; 7: selenase 84 lymphedema patients received selenium in addition to combined physical lymphedema therapy: 1 Week: 1,000 μg Se/d Week 2-3: 300 μg Se/d 3 months 100 μg Se/d Selenite given as oral solution; in addition to complex physical decongestive therapy. Selenium supplementation lowered the erysipelas incidence from 5% to 0%. 60 patients with secondary lymphedema and recurrent erysipelas 1 Week: 1,000 μg Se/d Week 2-3: 300 μg Se/d 3 months 100 μg Se/d Selenite given as oral solution; in addition to complex physical decongestive therapy. The erysipelas incidence in the Se group was 0% (Se levels in the normal range) as compared to control group at 50%. Selenase therapy replaced antibiotic management. Review Study 1: Day 1 4: 800 µg Se as selenite oral solution, Day µg Se as selenite oral solution led to a spontaneous reduction in the lymphedema volume and normalized the blood variables as part of a diminished release of free radicals. Study 2: Week 1: 1000 µg Se, week 2 + 3: 300 µg Se, the following 3 months: 100 µg Se, as selenite oral solution. Double-blind, placebo-controlled on mastectomized lymphedema patients receiving physical decongestive therapy: Selenite enhanced the efficacy of physical decongestive therapy, improving the range of motion and heat tolerance of the affected extremities.

65 References 65 Kazi TG, Kolachi NF, Afridi HI et al. Effects of mineral supplementation on liver cirrhotic/cancer male patients. Biol Trace Elem Res 2012; 150: Kiremidjian-Schumacher L, Roy M, Glickman R et al. Selenium and immuncompetence in patients with head and neck cancer. Biol Trace Elem Res 2000; 73: Kiremidjian-Schumacher L, Roy M. Effect of selenium on the immunocompetence of patients with head and neck cancer and on adoptive immunotherapy of early and established lesions. BioFactors 2001; 14: Measurements of levels of essential trace and toxic elements in the whole blood and serum of 144 male liver cirrhotic/cancer patients before and 60 days after trace element supplementation versus 120 healthy men. Liver cirrhotic/cancer patients had significantly lower Se and Zn levels than the healthy men (p < 0.001) as well as more than twice as high As and Cd levels. In all patients, oral Se and Zn supplements improved trace element concentrations and are capable of producing metabolic effects. Supplementation with selenium (200 µg/d) during therapy resulted in a significantly enhanced cell-mediated immune responsiveness. This was measured by the ability of the patient's lymphocytes to respond to mitogen stimulation, to generate cytotoxic lymphocytes, and to destroy tumor cells. By contrast, patients in the placebo arm of the study showed a decline in immune responsiveness both during as well as after completion of radiation therapy and/or surgery. Review: Se supplementation (200 µg/d) during therapy (surgery, radiation) for squamous cell carcinoma of the head and neck significantly enhanced cell-mediated immune responsiveness, whereas it declined in the placebo arm. Studies on mice have shown that local interleukin 2 therapy supplemented with selenium may represent an effective treatment modality to prevent recurrences at the sites of previously treated tumors.

66 66 References Kowalska E, Narod SA, Huzarski T et al. Increased rates of chromosome breakage in BRCA1 carriers are normalized by oral selenium supplementation. Cancer Epidemiol Biomarkers Prev 2005; 14: Lanfear J, Fleming J, Wu L et al. The selenium metabolite selenodiglutathione induces p53 and apoptosis: relevance to the chemopreventive effects of selenium? Carcinogenesis 1994; 15: Guideline Program in Oncology of the AWMF (Association of the Scientific Medical Societies of Germany), the German Cancer Society (Deutsche Krebsgesellschaft e.v.) and German Cancer Aid (Deutsche Krebshilfe e.v.). GoR level III "Guidelines for the diagnosis, treatment and follow-up care of breast cancer". AWMF Register no OL (status: 2 July 2012) In female BRCA1 carriers, the frequency of chromosome breaks was measured in cultured blood lymphocytes following in vitro exposure to bleomycin with and without selenium supplementation to test the mutagenicity of cells from BRCA1 carriers, and then compared with non-brca1 carriers. BRCA1 carriers had significantly greater mean frequencies of induced chromosome breaks per cell than non-brca1 carriers. Selenium supplementation lasting 1 to 3 months was able to greatly reduce this frequency to that of non-brca1 carriers. Oral selenium is therefore a good candidate for chemoprevention BRCA1 carriers. Selenodiglutathione (SDG), a metabolite of selenite, inhibits the growth of cancer cells more powerfully than the original substance. This was demonstrated on erythroleukaemia cells and an ovarian cell line. SDG has two independent mechanism of action. Firstly, it induces apoptosis, as can be illustrated by the alterations in cell morphology, membrane permeability and chromosome breakage. Moreover, it induces activity of the tumor suppressor gene p53. Women with mutations in one of these two breast cancer genes (BRCA) 1 and 2 have a lifelong risk of 50 to 80% for developing breast cancer and 10 to 40% of developing ovarian cancer.

67 References 67 Leroy B, Anderson M, Soussi T. TP53 mutations in human cancer: database reassessment and prospects for the next decade. Hum Mutat 2014; 35: Look MP, Musch E. Lipid peroxides in the polychemotherapy of cancer patients. Chemotherapy 1994; 40: 8 15 McKenzie RC, Arthur JR, Beckett GJ. Selenium and the regulation of cell signaling, growth, and survival: molecular and mechanistic aspects. Antioxid Redox Signal 2002; 4: Meyer HA, Endermann T, Stephan C et al. Selenoprotein P status correlates to cancer-specific mortality in renal cancer patients. PLoS One 2012; 7: e46644 Micke O, Bruns F, Mücke R et al. Selenium in the treatment of radiation-associated secondary lymphedema. Int J Radiat Oncol Biol Phys 2003; 56: Review: Over 50% of all tumor tissue carries a mutation or exhibits reduced expression of the p53 gene. Analysis of the TP53 mutation database focused on special mutations that had been overlooked in the past due to their rare frequency; To do so the authors evolved statistical methods to differentiate TP53 passenger mutations and artifactual data from true mutations. This process was deemed vital to release an accurate TP53 mutation database which will be an invaluable tool for clinicians and researchers. Repeat cycles of polychemotherapy with radical-generating compounds challenge the antioxidative capacity of cancer patients and cause them oxidative stress. This is detectable by elevated plasma concentrations of thiobarbituric-acid-reactive substances. Review of the basic mechanisms by which selenium regulates cell growth, gene transcription and cell death. Describes the synthesis and function of selenoproteins, the worldwide supply of selenium through dietary sources, selenium deficiency and toxicity. The authors retrospectively analyzed the selenium status of 41 patients with renal cell cancer and 21 controls. They found a correlation between higher tumor stage and lower selenoprotein P (SePP) and serum selenium concentrations. A low selenium status (SePP < 2.4 mg/l) at diagnosis was associated with a 5-year-survival of 20%. SePP and Se concentrations appear to be a prognostic parameters for renal cell cancer and should be accounted for in the diagnosis as they obviously affect the therapy regimen. 48 patients with acute and chronic lymphedema (upper extremities, head-and-neck region) after surgery and/or radiotherapy; 350 μg Se/ m 2 body surface/day for 4 to 6 weeks. Results: Reduction in edema volume and improvement in Skin-Fold Index, the five-point Miller score and quality of life.

68 68 References Mitra DK, Singh HP, Singh M et al. Reconstitution of naive T cells and type 1 function after autologous peripheral stem cell transplantation: impact on the relapse of cancer. Transplantation 2002; 73: Mücke R, Schomburg L, Glatzel M et al. Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. Int J Radiat Oncol Biol Phys 2010; 78: selenase Mücke R, Micke O, Schomburg L et al.: Multicenter, phase III trial comparing selenium supplementation with observation in gynecologic radia tion oncology follow-up analysis of the survival data 6-years after cessation of randomization. Integr Cancer Ther Epublication 11 Jul 2014 selenase Cytostatic therapy reduced the phenotypic and functional reconstitution of T cells and gamma-interferon (IFN)-producing memory T cells. A low number of naive cells and gamma-ifn producing memory cells correlates with the early recurrence of cancer. 81 patients with cervical and uterine cancer. 39 patients (active drug) received 500 µg Se/d during radiotherapy and 300 μg Se/d on the days without radiotherapy. 42 controls received nothing. The incidence of radiogenic diarrhea CTC Grade 2 (Common Toxicity Criteria) was significantly lower in the active drug versus the control group (20.5% vs. 44.5%; p = 0.04). In selenium-deficient cervical and uterine cancer patients, selenium supplementation during radiotherapy was effective in improving blood selenium status and in reducing the number of episodes and severity of radiotherapy-induced diarrhea. It did not diminish the effect of standard therapy. Follow-up analysis of trial published in 2010 on 81 patients cervical and uterine cancer receiving radiotherapy and sodium selenite (500 µg Se/d). 10-year-survival in the active drug group was 55.3% versus 42.7% in the control group (p = 0.09). The analysis demonstrated that selenium did not impair the efficacy of irradiation therapy or negatively affect long-term survival. In view of the selenium-mediated reduction in adverse reactions to radiotherapy, induced positive effects on RT-induced diarrhea, selenium should continue to be used in this group of patients.

69 References 69 Mücke R, Klotz T, Giedl J et al. Whole blood selenium levels (WBSL) in patients with prostate cancer (PC), benign prostatic hyperplasia (BPH) and healthy male inhabitants (HMI) and prostatic tissue selenium levels (PTSL) in patients with PC and BPH. Acta Oncol 2009; 48: Navarro-Alarcón M, López-Martinez MC. Essentiality of selenium in the human body: relationship with the different diseases. Sci Total Environ 2000; 249: Qiao YL, Dawsey SM, Kamangar F et al. Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. J Natl Cancer Inst. 2009; 101: Whole blood selenium levels were significantly lowered in all groups investigated, including healthy men (p = 0.01). Patients with prostate cancer (PC) had significantly lower selenium levels than healthy men (p = 0.04). Patients with benign prostatic hyperplasia (BPH), had lower selenium levels than healthy men (p = 0.13). No significant difference in levels existed between patients with BPH and PC (p = 0.67). Conclusion: The fact that the whole blood selenium levels were significantly lowered in all patients as well as in the healthy men supports the recommendation for selenium supplementation. Review on how selenium deficiency is connected with various degenerative diseases. Discussion about the optimal daily dietary intake needed to prevent or cure certain diseases conditions like cirrhosis, cancer, diabetes, or cardiovascular pathologies. Various epidemiological studies and animal experiments have indicated that selenium exerts a protective action against several degenerative diseases. 10-year follow-up on the Linxian trial (esophageal gastric cancer nutrition intervention trial, ; In 29,584 participants, 50 µg selenium, 30 mg vitamin E and 15 mg beta-carotene daily reduced cumulative mortality, cancer mortality and gastric cancer mortality). Up to 10 years after supplementation was ceased, selenium, vitamin E, and beta-carotene still had measurably evident effects on mortality; these benefits were consistently greater in younger participants.

70 70 References Rayman MP. Selenium and human health. Lancet 2012; 379: Rostkowska-Nadolska B, Pospiech L, Bochnia M. Content of trace elements in serum of patients with carcinoma of the larynx. Arch Immunol et Ther Exp (Warsz) 1999; 47: Roy M, Kiremidjian-Schumacher L, Wishe HI et al. Supplementation with selenium and human immune cell functions. I. Effect on lymphocyte proliferation and interleukin 2 receptor expression. Biol Trace Elem Res 1994; 41: Review: Selenium is incorporated into selenoproteins, exhibiting a myriad of anti-oxidant and anti-inflammatory functions and is involved in thyroid metabolism. Low selenium levels are associated with associated with an increased risk of mortality, poor immune status and cognitive impairments. A higher selenium status has antiviral effects, is essential for male and female reproduction, and reduces the risk of autoimmune thyroid disease and prostate, lung, colorectal, and bladder cancers. For supplementation to confer benefit, however, selenium intake must have been previously inadequate intake and its blood concentration must reach adequate levels. The content of arsenic, nickel, copper, selenium, zinc and iron was examined in the serum of 78 patients with laryngeal cancer, who were divided into four groups. The 17 patients in the control group underwent surgery for a deviated nasal septum. Compared with the control group, the patient group (group I) had higher pre-treatment serum concentrations of arsenic, nickel and copper, whereas those of selenium, zinc and iron were lower. In the post-treatment groups (II-IV, before treatment, after surgical treatment, after radiotherapy, after combined treatment, respectively), the highest serum concentrations of iron and zinc were found in the group after surgery. In all groups, the selenium levels were considerably lower than in the control groups. An eight-week dietary supplementation of 200 µg Se/d as sodium selenite or an in-vitro supplementation with M Se (as sodium selenite) was given to Se-replete humans. This resulted in a significant augmentation of the ability of peripheral lymphocytes to respond to stimulation with 1 µg/ml phytohemagglutinin or alloantigen (mixed lymphocyte reaction) as well as in their ability to express high-affinity interleukin 2 receptor on their surface.

71 References 71 Schrauzer GN, White DA, Schneider CJ. Cancer mortality correlation studies--iii: statistical associations with dietary selenium intakes. Bioinorg Chem 1977; 7: Sieja K, Talerczyk M. Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy. Gynecol Oncol 2004; 93: Siems WG, Brenke R, Beier A et al. Oxidative stress in chronic lymphoedema. Q J Med 2002; 95: These authors investigated in different 27 countries whether age-corrected mortalities from 17 different cancer types correlated with dietary selenium intakes. They found significant inverse correlations for colon, rectum, prostate, breast, ovary, lung cancers and leukemia, while weak inverse associations were found for pancreas, skin and bladder cancers. There were similar inverse correlations observed between cancer mortalities and whole blood selenium concentrations in healthy donors in the USA and other countries. These findings suggest that cancer mortality in industrialized nations might possibly be significantly lowered by doubling the selenium intake. 31 patients with ovarian cancer undergoingchemotherapy and simultaneous Se supplementation with 200 µg Se/d. The active drug group showed a significant increase in selenium in serum and hair, erythrocyte glutathione peroxidase activity, concentration of malondialdehyde and white blood cells. Additionally noted was a significant decrease in hair loss, flatulence, abdominal pain, weakness, malaise and loss of appetite. Compared to the control group, the blood of patients with chronic lymphedema contained lower concentrations of GSH and higher levels of GSSG (glutathione disulfide), MDA (malondialdehyde) (3-times higher) and HNE (4-hydroxy-2,3-trans-nonenal). These data demonstrated that the tissue of patients with chronic lymphedema has enhanced formation of reactive oxygen species and lipid peroxidation products. Chronic lymphedema therapy may be helped by strengthening antioxidative defense mechanisms.

72 72 References Smith ML, Lancia JK, Mercer TI et al. Selenium compounds regulate p53 by common and distinctive mechanisms. Anticancer Res 2004; 24: Stevens J, Waters R, Sieniawska C et al. Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies. Br J Haematol 2011; 154: Tsavachidou D, McDonnell TJ, Wen S et al. Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst 2009; 101: van den Brandt PA, Zeegers MPA, Bode P et al. Toenail selenium levels and the subsequent risk of prostate cancer: a prospective cohort study. Cancer Epidemiol Biomarkers Prev 2003; 12: Vollmar A, Dingermann T. Immunologie Grundlagen und Wirkstoffe. WVG, Stuttgart 2005 While differing widely in efficacy depending on their chemical form, selenium compounds show great potential in preventing prostate and other human cancers. Sodium selenite activates tumor suppressor protein p53 and additionally affects the regulation of proteins through phosphorylation. In this context, both methyl-seleninic acid and selenomethionine proved ineffective. These authors studied the value of selenium levels in predicting outcome in 430 patients with various hematological malignancies. Low selenium levels were associated with a worse outcome in patients with hematological malignancies. Nevertheless, selenium levels were not independently predictive, but show a multi-factorial effect. A randomized placebo-controlled phase IIA trial on 39 prostate cancer in patients before prostatectomy for which the authors created a preoperative model for prostatectomy tissue interrogation. Treatment in four groups: 200 µg Se/d, 400 IU vitamin C, both, or placebo. Effects of selenium and vitamin E on prostate tissue were demonstrated. Selenium intake re-increased expression of the tumor suppressor gene p53. The connection between prostate cancer and baseline toenail selenium levels was evaluated in 1,211 healthy subjects and 522 patients with prostate cancer. The prostate cancer risk was low in when selenium levels were higher. This inverse association proved more pronounced in ex-smokers than in smokers. These results confirm the hypothesis that a higher selenium intake might help reduce the risk for prostate cancer. Immunological basics.

73 References 73 Wallenberg M, Misra S, Björnstedt M. Selenium cytotoxicity in cancer. Basic Clin Pharmacol Toxicol 2014; 114: Warren AG, Brorson H, Borud LJ et al. Lymphedema: a comprehensive review. Ann Plast Surg 2007; 59: Winnefeld K, Dawczynski H, Schirrmeister W et al. Selenium in serum and whole blood in patients with surgical interventions. Biol Trace Elem Res 1995; 50: Zeng H, Cheng WH, Johnson LK. Methylselenol, a selenium metabolite, modulates p53 pathway and inhibits the growth of colon cancer xenografts in Balb/c mice. J Nutr Biochem 2013; 24: Zimmermann T, Leonhardt H, Kersting S et al. Reduction of postoperative lymphedema after oral tumor surgery with sodium selenite. Biol Trace Elem Res 2005; 106: This group investigated the cancer-specific cytotoxic effects of various selenium compounds: Not all selenium compounds are equally effective against cancer. The anticancer properties of inorganic selenium (primarily sodium selenite) are suprioer to those of organic selenium. A higher dose had a more effective on the tumor. In terms of tumor regression, our current knowledge is still limited. Prolonged intake of selenium is required for inhibition of tumourigenesis to be efficient. Sodium selenite holds the potential for multi-targeted chemotherapy regimens. A comprehensive review on lymphedema: Diagnosis, treatment, and options for patients unresponsive to conservative therapy. Selenium levels in whole blood dropped significantly after surgical interventions. Selenium supplementation before major surgical interventions followed by total parenteral nutrition helps patients combat the increase in oxidative stress reactions. An antibody microarray test was employed to investigate the molecular targets of methylselenol in human HCT116 colon cancer cells. Methylselenol modulates the expression of the key genes like p53 involved in the cell cycle and apoptosis and inhibits colon cancer cell proliferation as well as tumor growth. Cancer of the floor of the mouth or root of tongue with stage T3 and T4 after neck dissection with markedly lowered blood selenium levels; 10 patients receiving the active drug vs. 10 patients on placebo. On 1000 μg Se/d pre-, intraoperative as well as postoperative for 21 days, the active drug group showed less pronounced postoperative facial lymphedema, a significantly earlier reduction in edema, a decline in the rate of reintubations required, a reduction in postoperative bleeding and pneumonia. There was an inverse correlation between the extent and severity of edema and selenium levels as well as the glutathione peroxidase activity. No adverse reactions related to selenium.

74 74 biosyn Arzneimittel GmbH biosyn is the global market leader in high-dose selenium drugs This hidden champion supplies its high-revenue blockbuster selenase to 22 countries, primarily for oncology and intensive care medicine Founded in 1984, biosyn Arzneimittel GmbH was one of the first German biotechnology companies. Now it has around 60 employees in Germany and subsidiaries in Liechtenstein, Austria and the USA. Its portfolio encompasses some 30 products ranging from biotechnologically engineered medicines through chemotherapeutics to complementary drugs and food supplements for its main fields of intensive care medicine and oncology. The company's major concern is treating patients holistically. biosyn, a research-focused pharmaceutical company, puts up to 25 percent of revenues back into its pipeline. Its mission is to explore, evolve and market highly efficacious drugs with low side effects based on the most up-to-date evidence molecular biology has to offer. High-quality products from the world's first GMP-compliant production of sodium selenite In 2009, biosyn Arzneimittel GmbH was, and presumably still is, the first and only company in the world able to manufacture the active ingredient sodium selenite pentahydrate in internationally prescribed GMP quality thanks to biosyn's proprietary and patented production method. Its purification and crystallization technologies allow microbe-free production of high-quality trace element compounds under cleanroom conditions. This enables the production of injectable liquid pharmaceuticals to meet the particularly stringent demands on quality. biosyn currently manufactures anhydrous sodium selenite and sodium selenite pentahydrate for oral and parenteral formulations. The biosyn motto "we are research" not only symbolizes our dedication to medical and pharmaceutical progress, but also our drive to develop innovative manufacturing processes. The company markets its selenium drugs under the brand name selenase worldwide. GMP-compliant production of sodium selenite at biosyn: Vacuum drying system for targeted crystallization of metallic salts with defined portions of hydrated ingredients

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