It is an abnormal mass (growth) of body tissues, it may be

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2 What is cancer? It is uncontrolled growth of abnormal cells in the body due to genetic mutation and/or lack of control mechanisms that govern cell proliferation & differentiation. Normally immune system recognizes cancer cell & destroys them, if this normal process does not happen a tumor can grow What is Tumor? It is an abnormal mass (growth) of body tissues, it may be 1-Benign tumors [Non-cancerous] 2-Malignant tumors [Cancerous] Slowly growing (non-progressive) & - not invade nearby tissue - not travel to other area i.e. No metastasis - e.g. skin warts Soft fibroma of eye lid Rapidly grow & -invade nearby tissue -travel to other areas of body i.e. metastasis due to lack of adhesion molecules which are similar to glue that bind cells together e.g. pancreatic malignancy lymphoma leukemia 2

3 Cell cycle and principles of tumor growth All cells undergo division cycles during their life span. For any cell to survive it needs accurate, efficient & rapid DNA replication during cell cycle. 1-M phase: stage of mitosis 2-G 1 phase (Presynthetic): synthesis of all components required for DNA synthesis 3-G 0 phase (Resting phase): Recruitment strategy in cancer chemotherapy: it means that giving of specific stimulus to activate G 0 cell to enter the cycle at G1phase. e.g. giving of small dose estrogen in treatment of breast cancer. 4-S phase: DNA replication (synthesis) 5-G 2 phase (post synthetic or Premitotic): preparation for mitosis 3

4 Check points respond to cellular damage by 1-Slowing cell cycle to give time for repair 2-Inducing transcription of genes that facilitate repair So loss of check point results in: chromosomal instability, mutation & cancer cells 1. Positive regulators of cell cycle: Are major proteins that control switches for cell cycle, help cell to pass check points causing cell to move from G 1 to S or G 2 to M i.e. cell division e.g. 1- Growth factors & hormones 2- Cyclin- dependent kinase (CdK), cyclins. 1. Negative regulators [tumor suppressor genes]: Are protein that prevent cell from passing check points by binding to CdK, cyclin & inhibit their action, these proteins are induced by many genes e.g. P27, P53 & retinoblastoma [Rb] gene These genes stop cycle at checkpoints allowing for repair and if repair fail apoptosis is initiated. Cell cycle control The Cell cycle progress depends on balance between positive and negative regulatory forces 4

5 P27 is a protein that binds to cyclin and CDK blocking entry into S phase P53 is a protein that blocks the cell cycle at the M checkpoint if DNA is damaged. If the damage is severe this protein can cause cell suicide (apoptosis). A p53 mutation is the most common in cancer cells 1 st line defense against mutation Rb is a tumor suppressor protein, inhibit cell cycle progression until a cell is ready to divide, hence retinoblastoma protein (prb) is phosphorylated, it becomes inactive and allow cell cycle progression. The genesis of cancer cells -Normal cell turns into cancer cell because of mutation in its DNA, 3-7 different mutations must occur in a single cell to become cancerous. -There are two main genetic change cancer 1. Inactivation of tumor suppressor genes 2. Activation of proto-oncogenes to oncogenes 5

6 Inactivation of tumor suppressor genes p53 gene acts as a policeman in the nucleus, if DNA is damaged (mutation) the protein of p53gene arrest DNA replication at checkpoint 1 allow time for repair If the repair is failed p53 activity triggers cell suicide (apoptosis) When P53 is altered by mutation (most common in cancer cell) P53 inactivation stop its function Cancer So There is a relation between genes, cell division, and cancer Activation of proto-oncogenes to oncogenes Proto-oncogenes are genes that normally control cell division and differentiation The RAS (Retrovirus Associated DNA Sequence) gene is an example of proto-oncogenes this gene codes for Ras protein that regulate cell growth, differentiation and apoptosis Mutation can convert proto-oncogenes into oncogenes 6

7 What are the common characteristics of cancer cells: 1-Uncontrolled proliferation. (not response to apoptotic signals) 2-Dedifferentiation. [Less differentiated cell morphology) & loss of function. 3-Evasion of the immune system. 4-Vascularization [angiogenesis]. Formation of new blood vessels to supply O 2 & nutrients to cancer cells. The process starts when tumor cell release angiogenic proteins that trigger endothelial cells of the capillaries to release protein growth factor Capillaries differentiate and begins to grow. 5-Mobility and invasiveness. A.Normal cells that escape accidentally lose their survival signals and undergo apoptosis. B.Cancer cells secrete metalloproteinase that breaks tissue matrix enabling the cancer cells to slip through. 6-Metastasis: Tendency to spread to other parts of the body. e.g. Prostate cancer metastasis to pelvic bone. 7

8 The different types of Cancer? Carcinoma Sarcoma Leukemia: Malignancy in epithelial cells that line body organ e.g. Skin, lung, stomach, intestine & Blood vessels Squamous cell carcinoma affect upper layer of skin Cancer that develops in connective tissue e.g. muscles, bone & cartilage Soft tissue sarcoma develop as a lump under the skin Carcinogens (Factors causing cancer) Develop in blood cells, is the only cancer where no tumor is formed Lymphoma: The most common blood cancer that develop in lymphatic system The incidence, geographic distribution and behavior of specific types of cancer are related to multiple factors, including sex, age, race, genetic predisposition and exposure to environmental carcinogens (lead to mutation cancer growth). 1. Cigarette smoke 2. Diet (saturated fats, high salt intake, ), overweight 3. Alcohol acetaldehyde genetic mutation 4. Pathogens (oncoviruses): Hepatitis B, C viruses liver cancer. HPV cervical cancer HIV Kaposi s sarcoma. Helicobacter pylori stomach cancer. 4. Radiation: X-rays, Hiroshima, Nagasaki, Chernobyl 5. Pollution, industrial chemical e.g. benzene, asbestos, azo dyes. 8

9 *Genetic accident some gene mutations associated with cancer are inherited, include: Oncogenes genes that cause malignancy proto- oncogenes normal gene may be converted to oncogenes Tumor suppressor genes Repair genes *Steroid hormones (Waist circumference < 102cm for men < 88 cm for women) In women estrogen risk of estrogen dependent breast & uterine cancer NB: Hormone replacement therapy (estrogen, progesterone) to treat S &S of menopause increase the risk Breastfeeding for years might slightly lower the risk of breast cancer Obesity? (increase estrogen level) Estrogen produced mainly from: 1-ovaries 2-Fat tissue high amount 9 small amount

10 Cancer staging it depends on cell structure & its metastasis TNM staging system is common system to measure the extent of cancer spread [metastasis] or How far the cancer spread. T refers to the tumor size N refers to no.of lymph nodes involved M refers to metastasis Stage 0 Pre-cancer i.e. genetic mutation only Stage 1 Small tumor found only in the organ where it start Stage 2 Large tumor may or may not spread to lymph node Stage 3 Large tumor that spread to lymph node but NO metastasis Stage 4 More large tumor, L.N. involved, metastasis NB: staging is a guide for the treatment prognosis (the lower the stag the better the prognosis) 10

11 " *Cancer Grading? It depends only on structure of cells It predicts how much cancer cells differ from normal cells in appearance Grading the aggressiveness of cancer when examined microscopically & High grade when more cancer cells differ from normal cells in appearance The American joint commission on cancer (AJCC) recommends the following grading: GX: grade cannot be assessed G1: cells well differentiated...cancer cell looks fairly normal G2: cells moderately differentiated...are less normal in appearance but recognizable G3: cells poorly differentiated...differ from normal cells in shape G4: cells undifferentiated (very immature)..completely unrecognizable 11

12 A- Goals of treatment: 1. Cure or eradication of every neoplastic cell. Principles of cancer chemotherapy 2. Palliative treatment to symptoms & survival & improve quality of life. 3. Adjunctive therapy : to eradicate microscopic cancer after surgery. a. Hit fast and hit hard we treat early by using all drugs and don t stop one of them B-Indication of treatment Chemotherapy are indicated when neoplasm are disseminated and not amendable to surgery. Chemotherapy used after surgery and radiation to attack micrometastasis. C-log kill The earlier the treatment the better the prognosis Destruction of cancer cells by cytotoxic drugs following 1 st order kinetic. i.e. given dose of the drug kills a consistent fraction ( %) of cells, not constant number e.g. when the drug kills % so 0.001% will remain, not removed by immunity so additional treatment is required to totally eradicate! tumor cells. log cell kill of drug more effective is the drug. 12

13 D-Advantages of drug combination are to efficacy resistance overlapping toxicities & the danger of toxic effect to normal cells. Drugs with different mechanism of action & quantitatively different toxicities are usually combined in full dose Methotrexate [myelosuppresion] +vincristine [neurotoxicity] Drugs with similar toxicity such as myelosuppresion can be combined safely only by reducing the dose of each E- Drugs usually are given intermittently in high doses for several courses with intervals of 2-3 weeks between courses? To allow bone marrow to regenerate during the interval Less immunosuppressive More effective than continuous low dose E.g. FAC-V regimen for breast cancer (Fluorouracil, Actinomycin D, Cyclophosphamide & Vincristine) used 6 cycle 1 month apart. 13

14 Problems associated with chemotherapy 1-Resistance Acquired resistance results from an adaptive change in neoplastic cells It is minimized by short term, intensive, intermittent therapy with combinations of drugs 2-Multidrug resistance: What is MDR? It is an adaptive survival mechanism due to increase expression of an ATPdependent membrane efflux pump called p-glycoprotein that pumps drug out of the cell e.g. (doxorubicin, vinblastine, dactinomycin, ) Cisplatin don t produce this type of resistance Ontogen (ONT-093). It is an investigational new drug, a P-glycoprotein pump inhibitor, for the potential reversal of multidrug resistance in patients undergoing cancer chemotherapy. it is not yet approved although it pass all phases of clinical trials (volunteer, pt) 14

15 3-Toxicity: Cytotoxic drugs affects normal cells undergoing rapid proliferation (e.g., bone marrow, mucosal surfaces & hair follicles) 4- Infertility & teratogenicity: Antineoplastic drugs impair fertility & increase the incidence of fetal abnormalitie 5-Second malignancy: Most antineoplastic drugs are mutagens. Neoplasms may arise 10 or more years after the original cancer was cured. 15

16 Cancer treatment 1- Surgery 2- Radiotherapy 3- Cytotoxic chemotherapy 4- Endocrine therapy 5- Immunotherapy 6- Biological therapy 7- Radioimmunotherapy 8- Gene therapy 9- Adenovirus 10- Angiogenesis inhibitors Cancer treatments vary, depends upon 4 main factors - Type of cancer - Stage of cancer - The overall pt condition - Goal of treatment 16

17 Cytotoxic chemotherapy I- Classification according to mechanism of action Mechanism Examples 1. Direct damage to DNA Platinum compound, cytotoxic antibiotic, alkylating agents & etoposide 1. Antimetabolites : stop synthesis of DNA precursors Methotrexate, 5-fluorouracil & 6 mercaptopurine 1. Spindle poison or microtubules inhibitors [mitosis inhibitors ] Vinblastin, vincristine, paclitaxel II- Classification according to Cell cycle specificity 1. Cell cycle specific: are effective only in replicating cell e.g. - antimetabolites is effective S phase - bleomycin is effective in G2 & M phase also in non dividing cells at G0 -vinca alkaloids act in mitosis 1. Cell cycle non specific Kill cells if resting or actively cycling they are effective for solid tumors, high Growth fraction malignancies e.g. alkylating agents &doxorubicin. Describe the relevance of cell cycle kinetics to mode of action of anticancer drugs? 17

18 Cytotoxic chemotherapy A- Antimetabolites (Stop the synthesis of DNA precursors) 1- Folic acid antagonists Methotrexate (Methotrex, Unitrexate) Mechanism inhibits DHFR prevents the formation of THF essential for synthesis of purines DNA synthesis & cell death Uses 1- Acute lymphocytic leukemia 2- Choriocarcinoma (malignant trophoblastic cancer usually of the placenta) 3- Rheumatoid arthritis ( Immunosuppressant) (7.5 mg p.o weekly, max 20mg) 18

19 Toxicity 1- Megaloblastic anemia 2- Hepatic damage 3- Bone marrow depression 4- Alopecia These adverse effects can be reversed by: intake of folinic acid (leucoverin; a form of THF) which bypass the inhibited reductase & folate pool Drug resistance???? Resistance to methotrexate can be developed by one or more of the following: 1- synthesis of DHFR through ed gene expression 2- affinity to DHFR by gene mutation 3- influx of methotrexate by a change in the carrier mediated transport To overcome such resistance higher doses of methotrexate are recommended 19

20 A- Antimetabolites 2- Purine antagonists e.g. A- 6- Mercaptopurine (6-MP) (purinethol) Mechanism 6-MP acts as a normal substrate for the enzyme Hypoxanthine-Guanine Phosphoribosyltransferase (HGPTase), Converted into 6-mercaptopurine ribose phosphate (6MPRP) which inhibits the enzyme phosphoribosylpyrophosphate amidotransferase) involved in synthesis of purine bases. Uses Toxicity Acute lymphocytic leukemia & crohn s disease Hyperuricaemia, hepatic damage & bone marrow depression Interactions 6-MP is metabolized in the liver by xanthine oxidase enzyme thiouric acid Allopurinol (used to prevent gout) inhibits xanthine oxidase, the enzyme that metabolizes 6-MP thereby inhibit renal damage The dose of 6-MP should be reduced in patients receiving allopurinol?? B-Azathioprine (Imuran ) (immunosuppressant) prodrug produce its effect after conversion to 6-MP 20

21 A- Antimetabolites 3- Pyrimidine antagonists e.g.5- Fluorouracil ( Fluorouracil, Ezadex ) Cytarabine (-DNA Polymerase.ALL) & fludarabine (-DNA polymerase & DNA primase (- )of DNA synthesis, cell destruction.cll, NHL) Mechanism 5FU is converted into fluorodeoxyuridine monophosphate which inhibits thymidylate synthetase (dump.dtmp) thymidine synthesis. Uses 1- Solid tumors (breast, colon & stomach) 2- Topically in skin sarcoma CMF Breast cancer Toxicity: Stomatitis, diarrhea & bone marrow depression dermatopathy {hand-foot syndrome} Erythematous desquamation of palm & soles causing redness, swelling, and pain 21

22 B- Alkylating agents Mechanism They transfere alkyl group to cellular DNA -DNA fragmentation by inducing repair enzymes -Formation of cross-linking (inter or intra strand) prevents DNA separation for synthesis or transcription. -Induce Miss pairing of the nucleotides leading to permanent mutations and hence apoptotic cell death (A..T G C alkylated G base pair with T base ) Classification & uses 1- Nitrogen mustard e.g., Mechlorethamine (Mustin), Cyclophosphamide (Endoxan), chlorambucil ( Leukeran) & ifosfamide Used in Hodgkin's lymphoma (ch by presence of a Reed-Sternberg cell in the tissue samples) 2- Nitrosoureas e.g., Carmustine (I.V) & Lomustine (p.o) Used in brain tumors.are lipid sol, cross BBB 3- Alkylsulphonates e.g., Thiotepa Used in chronic leukemia 4- Triazenes e.g., Dacarbazine (Decarb) Used in Hodgkin's lymphoma & brain tumor 22

23 5- Platinum compounds (intercalating agents.crosslink DNA like alkylating agent) a- Cisplatin ( Platinol) Drug of choice in metastatic testicular cancer** b- Carboplatin Used to treat ovarian & lung cancer c- Oxaliplatin Used in colorectal cancer Toxicity Cyclophosphamide Carmustine Cisplatin * Carboplatin* Alopecia & hemorrhagic cystitis Nausea & vomiting Nephrotoxicity, neurotoxicity, severe N,V & ototoxicity hearing loss Myelotoxicity haemologic cyctitis (due to acroline metabolite) & it is avoided by fluid intake & SH donor as mesna (sodium 2 mercapto-ethane sulfonate) or acetylsysteine which interact with acroline forming non toxic compound Thiol compound e.g. Amifostine ameliorates Cisplatin induced nephrotoxicity without decreasing it antitumor effect 23

24 C- Anticancer (cytotoxic) antibiotics Examples: Doxorubicin (Adriamycin), Daunorubicin,streptozotocin (pancreatic tumor) Dactinomycin (Actinomycin D)& Bleomycin (Bleocin): mix of metal chelating glycopeptides, form complex with iron generates active oxygen free radicals that form single and double-stranded breaks in DNA i.e. Bleomycin break DNA by oxidative process. Mechanism They intercalate between adjacent base pairs of DNA, thus block DNA synthesis, inhibition of transcription & induction of mutations. (direct action on DNA) (intercalation interferes with the action of topoisomerase-ii (DNA gyrase), resulting in strand breaks and cell death). Bind to cell membrane lipid peroxidation ROS release Uses Breast, ovarian, bladder & lung cancer NB: like anthracyclines, Etoposide acts by A- inhibiting Topoisomerase II (which aids in DNA uncoiling), break B- formation of a complex with DNA and prevents re-ligation of the DNA strands DNA strands to Toxicity (DLT) Doxorubicin Bleomycin Etoposide Etoposide used in testicular, lung cancer & leukemias. plus GIT upset, stomatitis & alopecia Cardiotoxicity (due to generation of FRs), prevented by The iron chelator (dextrazone) Pulmonary fibrosis (10% of Pts), in contrast to most anticancer drugs, it causes little myelosuppression myelosuppression 24

25 Drugs used in combination to treat testicular cancer Combining drugs that damage DNA directly e.g. Cisplatin, Bleomycin with drugs that inhibit topoisomerase II, e.g. etoposide have powerful synergistic anticancer effect This synergism related to the role of topoisomerase in repairing DNA damage or to combined ability of these classes to induce sufficient DNA damage to trigger apoptosis These drugs have different mechanism of action and different side effects so can be combined in a full dose Cisplatin..less myelosuppression but more nephrotoxicity, Bleomycin..little myelosuppression but pulmonary fibrosis showed by shortness of breath Etoposide.myelosuppression 25

26 D- Plant alkaloids Spindle poison or microtubules inhibitors Examples: Vinblastine & Vincristine & Taxoids (paclitaxel & docetaxel) Mechanism: Uses: They arrest mitosis by binding to the protein tubulin in the microtubules - Acute leukemia & lymphoma - Testicular & breast cancer Vincristine Has little myelotoxicity but cause neurotoxicity (peripheral neuropathy) 26

27 Adverse effect of chemotherapy 1)Anorexia. nausea and vomiting 2)Bone marrow depression a.neutropenia corrected by filgrastim (GCSF. Neutrophils) b. Anaemia corrected by Erythropoietin (Epogen) a.thrombocytopenia corrected by Interleukin-11 (neumega) b.delayed wound healing due to immunosuppression 3)Gut epithelium diarrhea and mouth ulcers 4)Hyperuricaemia 1- fluid intake 2-alkalinization of urine 3-allopurinol 5)Alopecia 6)Sterility & teratogenicity 27

28 Treatment of cytotoxic drugs associated Nausea and vomiting: 5-HT3 receptor antagonists e.g. Ondansetron and Granisetron Phenothiazines e.g. Prochlorperazine D2 receptor antagonists e.g. Metoclopramide Benzodiazepines e.g. Lorazepam Corticosteroids e.g. Dexamethasone 28

29 Hormones & their antagonists (endocrine therapy) 1- Estrogen e.g., Ethinyl estradiol, Diethylstilbesterol. LH production synth of testosterone Used in treatment of prostate cancer breast cancer?? 2- Androgens e.g., Testosterone propionate Used in treatment of breast cancer 3- Antiestrogens - e.g., Tamoxifen ( Nolvadex ) & Fluvestrant Used in treatment of breast cancer. Ineffective in pre-menopause?? 4- Antiandrogens e.g., Cyproterone (Androcur), Flutamide & Nilutamide - Used in treatment of prostate cancer 29

30 6- Aromatase inhibitors - e.g., Anastrozole (Arimidex) & Letrozole (Femara) androstenedione ----Aromatase enzyme--- estrogen - Used in breast cancer postmenopausal breast cancer 30

31 Immunotherapy Rituximab (Rituxan, Mabthera) Monoclonal antibody effective in treatment of chronic lymphocytic leukemia (CLL) Binds to the CD20 antigen on the abnormal B lymphocytes & recruits immune effector functions to mediate B-cell lysis I.e. antibody-dependent cell mediated cytotoxicity (ADCC). Trastuzumab (Herceptin 440 mg) Monoclonal antibody that blocks the effects of the HER2 (human epidermal growth factor receptor 2), which sends growth signals to breast cancer cells Cetuximab (Erbitux) Monoclonal antibody that has recently been approved to treat colorectal cancer It exerts anti-neolplastic effect by targeting the epidermal growth factor receptor on the surface of cancer cells 31

32 Radio-immunotherapy Ibritumomab tiuxetan (Y-90 or In-111 Zevalin) Combination of a monoclonal antibody directed against the CD20 antigen (a protein found on the surface of normal & malignant B- lymphocytes) with the radioisotopes yttrium-90 or indium-111 Used in B-cell non-hodgkin s lymphoma (NHL) After Y-90 ZEVALIN (the therapeutic component of the ZEVALIN regimen) enters the bloodstream, the monoclonal antibody Ibritumomab recognizes and attaches to the CD20 antigen, allowing beta radiation emitted by the Yttrium-90 isotope to penetrate and damage the B-cell as well as neighboring cells this KN as crossfire effect. 32

33 Biological therapy It stimulates the immune system so that it can better recognize & destroy cancer cells Examples: Interferon-α Activates natural killer cells Used in non-hodgkin's lymphoma & melanoma Used also in patients with hepatitis C Interleukin-2 Stimulates proliferation of T-lymphocytes Used in renal cell carcinoma 33

34 Gene therapy Introduction of genes into living cells to cure cancer Example Replacement of defective tumor suppressor gene by a normal one in liver cancer Oncolytic virus therapy Onco = cancer Lytic = killing A virus having the ability to infect and lyse cancer cells, while leaving normal cells unharmed (targeted therapy). it also stimulate host anti-tumor immune response Examples Adenovirus Retrovirus Vaccinia virus 34

35 Angiogenesis inhibitors Bevacizumab (Avastin) first anti-angiogenic drug used in kidney cancer Monoclonal antibody It attaches to and stops vascular endothelial growth factor (VEGF) from stimulating the formation of new blood vessels Adverse effects include hypertension, stomatitis & diarrhea Sunitinib (Sutent) inhibits cellular signaling by targeting multiple receptor tyrosine kinases (RTKs). These include all receptors for platelet-derived growth factor (PDGF-Rs) and vascular endothelial growth factor (VEGFRs), which play a role in both tumor angiogenesis and tumor cell proliferation. therefore reduces tumor vascularization and triggers cancer cell apoptosis and thus results in tumor shrinkage. 35

36 Thank you 36

37 1-malignant tumor can be distinguished from Benign tumor by : a- can invade near by tissue b- dedifferentiation & loss of function c- invasiveness d- vascularization & metastasis e- all of them. 2-which of the following are considered risk factors for developoing of cancer a-use of deoderants b-use of mobile phone c-genetic mutation d-exposure to industrial chemicals like asbestos e- C &D 3-all of the following are antimetabolite except a- methotrexate b- 6mercaptopurine c- doxorubicin d- fluorouracil 37

38 4-cancer grading a.measures the extent of spread of cancer b. measures the aggreasivenes of cancer c.both are correct d.none is correct 5-true about p-53 gene a-mutation in p-53 is the most frequent mutation in cancer cells. b-cancer that express p-53 are not responsive to chemotherapy c-mutation inp-53 is anexample of activation of proto-onchogene to oncogene d-all are correct 6-which of the following agents used in drug combination to treat testicular carcinoma is most likely to cause nephrotoxicity A-Etoposide B-Belomycin C-Vinblstine D-Cisplatin 38

39 7-Allopurinol a.inhibit the synthesis of uric acid b.is a xanthine oxidase inhibitor c.may be used with cytotoxic antineoplastic drugs d.all of the above 8-Nitrosourea are used in brain tumor as they a- are highly lipid soluble b- pass in urine c-are ionized drugs d-treat bacterial meningitis 39