Biochemical principles of antineoplastic treatment. Dr. Martin Matějů

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1 Biochemical principles of antineoplastic treatment Dr. Martin Matějů

2 Aim of this message: is to clearly and briefly demonstrate basic principles of distinct therapeutical modalities of cancer treatment the purpose of this message shouldn t be to remember all the names of antineoplastic drugs but to acquire awareness of their function, targeted structures and possible use in complex cancer treatment

3 Problem? It isn't possible to avoid overlapping in different fields of knowledge like: farmacology molecular biology physiology and pathophysiology oncology and other clinical specialization

4 Problem? It isn't possible to avoid overlapping in different fields of knowledge like: farmacology molecular biology physiology and pathophysiology oncology and other clinical specialization NO! It is a challenge and basic need for a student of 3rd year to intergate acquired knowledge!!!

5 Possible modalities of cancer therapy Local therapy limited disease surgery radiotherapy System therapy advanced disease chemoterapy imunoterapy hormonal therapy targeted therapy

6 Tendency to adjust therapy to factual patient Choice of therapeutic modality and type of antineoplastic drug depends on: 1. guidelines (international- NCCN, national CZ Blue book, hospital ) 2. concrete situation (PS, age, comorbidity, mobility, profession ) 3. economic aspects (similar response rate two different drugs and significant difference in cost) Generally one-sided view is always insufficient.

7 Example of NCCN guideline

8 Surgery best antitumor treatment It is the surgeons experiences that count - training - R0 resection? - number of lymphatic nodes obtained at lymphadenectomy at early stage of cancer often a curative intervention without need of additional antitumour therapy in advanced disease a debulking (cytoreduction) intervention can be performed, e.g. debulking in OC or nephrectomy in metastatic renal carcinoma increase the success rate of subsequent therapy

$(protons) external beam RT, brachytherapy, stereotactic radiation, Dose (1 Gy=1 J/ kg), fractionation Mechanism of action: target = DNA damage is caused by photon, electron,$ proton or ion beam : 1) directly 30 % - more severe DNA damages (double-strand breaks) 2) indirectly 70 % - by ionization of H2O molecules that forms free radicals, notably

proton or ion beam : 1) directly 30 % - more severe DNA damages (double-strand breaks) 2) indirectly 70 % - by ionization of H2O molecules that forms free radicals, notably

9 Radiation therapy gama radiation in therapeutic use since 1903 Cobalt emitter (Co 60) > medical linear accelerator Energy transmitter : photons -> electrons ->future- hadrons (protons) external beam RT, brachytherapy, stereotactic radiation, Dose (1 Gy=1 J/ kg), fractionation Mechanism of action: target = DNA damage is caused by photon, electron, proton or ion beam : 1) directly 30 % - more severe DNA damages (double-strand breaks) 2) indirectly 70 % - by ionization of H2O molecules that forms free radicals, notably hydroxyl radical (but also hydrogen peroxide, superoxide radicals), which then damage both backbones and bases One of major limitations of RT is low oxygen status (O2 is a potent radiosensitizer)

10 Radiation therapy even cells have mechanisms for repairing DNA damage -> double-strand breaks are the most significant technique in modifying cell characteristics cancer cells generally reproduce more, and have a diminished ability to repair sub-lethal damage compared to most healthy cells > unrepaired double-strand breaks accumulate - short repairment time - oversaturated repair capacity - inccorect repair ability to repair damaged double-strand breaks correspond with radiosensitivity of the tissue

11 Radiation therapy mitotic cell death (DNA damage is inherited, cell may die after several divisions -> latency according mitotic activity of irradiated tissue) instant cell death (intermitotic death) e.g. lymphocytes, germinal cells and derived tumors - most radiosensitive are cells passing G2 /M phase and G1/S phase - on the contrary the most radioresistent cells are either in G0 or S phase of cell cycle

Chemotherapy advancement after WW I where Sulfer Mustard (Mustard gas) alkylating agent was used for the first time in general cancer cells reproduce faster and have a decreased ability to repair

12 Chemotherapy advancement after WW I where Sulfer Mustard (Mustard gas) alkylating agent was used for the first time in general cancer cells reproduce faster and have a decreased ability to repair sublethal DNA damage starting point in thinking about CHT CHT affects NONSPECIFICALLY fast dividing cells of the body => therefore specific side effects : - temporary depression of hematopoesis (bone marrow) - GIT intolerance (cells of intestinal mucosa) - alopecia (cells of hair follicle)

13 Chemotherapy list Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplasmatic agents) Platin based alkylating like agents Nonclasical cisplatin, karboplatin, oxaliplatin dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, CDK, PI, PARP

14 Examples of combined CHT regimen ABVD AC BEACOPP BEP CA CAF CAV CBV CHOP CHOP-R COP CMF COPP EC ECF EP FEC MAYO (FL) FOLFOX FOLFIRI Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine Adriamycin (doxorubicin), cyclophosphamide Bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), procarbazine, prednisone Bleomycin, etoposide, platinum agent (cisplatin) Cyclophosphamide, Adriamycin (doxorubicin) (same as AC) Cyclophosphamide, Adriamycin (doxorubicin), fluorouracil (5-FU) Cyclophosphamide, Adriamycin (doxorubicin), vincristine Cyclophosphamide, BCNU (carmustine), VP-16 (etoposide) Cyclophosphamide, hydroxydoxorubicin (doxorubicin), vincristine (Oncovin), prednisone CHOP + rituximab Cyclophosphamide, Oncovin (vincristine), prednisone Cyclophosphamide, methotrexate, fluorouracil (5-FU) Cyclophosphamide, Oncovin (vincristine), procarbazine, prednisone Epirubicin, cyclophosphamide Epirubicin, cisplatin, fluorouracil (5-FU) Etoposide, platinum agent (cisplatin) Fluorouracil (5-FU), epirubicin, cyclophosphamide Fluorouracil (5-FU), leucovorin (folinic acid) Fluorouracil (5-FU), leucovorin (folinic acid), oxaliplatin Fluorouracil (5-FU), leucovorin (folinic acid), irinotecan Hodgkin's lymphoma Breast cancer Hodgkin's lymphoma Testicular cancer, germ cell tumors Breast cancer Breast cancer Lung cancer Lymphoma Non-Hodgkin lymphoma B cell non-hodgkin lymphoma Non-Hodgkin lymphoma in patients with history of cardiovascular disease Breast cancer Non-Hodgkin lymphoma Breast cancer Gastric cancer and oesophageal cancer Testicular cancer, germ cell tumors Breast cancer Colorectal cancer Colorectal cancer Colorectal cancer

15 Targets of classical chemotherapeutics

16 Targets of non - classical chemotherapeutics

17 Inhibition of mitosis (M phase) Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplasmatic agents) Platin based alkylating like agents Nonclasical cisplatin, karboplatin, oxaliplatin dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, CDK, PI, PARP

interfere with growth of microtubulus inhibit assembly - In higher concentrations even

18 Vinca alkaloids Vinorelbin - Spindle poison derived of plant Catharanthus - they are now produced synthetically and used as drugs in cancer therapy - they bindβsubunit of tubulin and interfere with growth of microtubulus inhibit assembly - In higher concentrations even depolymerize microtubules Vinblastine,Vincristine, Vinorelbine breast ca, NSCLC Catharanthus roseus Tubulin

19 Inhibition of mitosis (M phase) Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplsmatic agents) Platin based alkylating like agents Nonclasical cisplatin, karboplatin, oxaliplatin dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, CDK, PI, PARP

stabilize microtubules of mitotic spindle and arrest the dividing cells in metaphase/anaphaze crossing -

20 Taxanes Paclitaxel - produced by Pacific yew (paclitaxel) - chemically: diterpens - by bindingβsubunit of tubulin they stabilize GDP-bound and increase tubulin s afinity of tubulin to other units, therefore they stabilize microtubules of mitotic spindle and arrest the dividing cells in metaphase/anaphaze crossing - they are believed to be radiosenzitisers Docetaxel, Paclitaxel Breast Ca, OC, prostatic Ca, NSCLC Taxus - yew

21 Antifolates (S phase) act by inhibiting the metabolism of folic acid Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplasmatic agents) Platin based alkylating like agents Nonclasical cisplatin, karboplatin, oxaliplatin dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, CDK, PI, PARP

22 Antifolates Metotrexate MTX is an antimetabolite and antifolate drug used in treatment of cancer (hematological malignancies) and autoimmune diseases it has similar structure to folic acid, therefore it competitively and irreversibly inhibits dihydrofolate reductase (DHFR), affinity of methotrexate for DHFR is about 1000x Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate Folic acid is needed for the de novo synthesis of the nucleoside thymidine inhibits the synthesis of DNA, RNA, thymidylates, and proteins dihydrofolate Methotrexate tetrahydrofolate

23 Antifolates pemetrexed Pemetrexed NSCLC and mesotelioma chemically similar to folic acid inhibits 3 types of enzymes: 1) DHFR 2) thymidylate synthase (deoxyuridin + N5,N10 metyl 4HF => dtmp) 3) glycinamide ribonukleotid formyltransferase

24 Leucovorin = Folinic acid 5-formyl derivative of tetrahydrofolic acid it is readily converted to other reduced folic acid derivatives (e.g. tetrahydrofolate), it does not require the action of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition DHFR by drugs such as methotrexate is an adjuvant used in cancer chemotherapy involving the drug methotrexate it is also used in synergistic combination with the chemotherapy agent 5FU in GIT cancer Folinic acid Folic acid

25 Purin analogues (S phase) Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplasmatic agents) Platin based alkylating like agents cisplatin, karboplatin, oxaliplatin Nonclasical dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, CDK, PI, PARP

26 Purin analogues interfere with the cell's ability to process DNA: Pentostatin - mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase - hairy cell leukemia Pentostatin Mercaptopurin - is converted to the corresponding ribonucleotide - 6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism - leukemia, non H lymfoma.. Mercaptopurin

27 Pyrimidin analogues (S phase) Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplasmatic agents) Platin based alkylating like agents cisplatin, karboplatin, oxaliplatin Nonclasical dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, CDK, PI, PARP

28 Pyrimidin analogues URACIL 5FU thymidylate synthase inhibitors - 5FU, Capecitabin - Ca GIT, BC DNA polymerase inhibitor - cytarabine hematologic mlg. ribonucleotide reductase inhibitor - gemcitabin pancreatic cancer hypomethylating agent - azacitidin - MDS CYTARABINE Gemcitabine azacitidine

29 Ribonucleotide reductase inhibitor (S phase) Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplasmatic agents) Platin based alkylating like agents cisplatin, karboplatin, oxaliplatin Nonclasical dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, CDK, PI, PARP

30 Ribonucleotide reductase inhibitor Hydroxyurea - reduction of production of deoxyribonucleotides via inhibition of the enzyme ribonucleotide reductase - used in myeloproliferative disorders

31 Isomerase's inhibitors (S phase) Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplasmatic agents) Platin based alkylating like agents cisplatin, karboplatin, oxaliplatin Nonclasical dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, CDK, PI, PARP

inhibitors: topotecan OC + SCLC irinotecan Ca colon Topoisomerase II inhibitors:

32 Isomerase's inhibitors - interfere with the action of topoisomerase enzymes that leads to either single (TI) or double stranded (TII) breaks Topoisomerase I inhibitors: topotecan OC + SCLC irinotecan Ca colon Topoisomerase II inhibitors: etoposid Lung ca, testicular tumors Doxorubicin breast ca Topoisomerase I etoposid Topoisomerase II

33 Antracyclines = antracycline ATB Derived from Streptomycetes bacteria have three mechanisms of action: 1. inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells 2. inhibits topoiosomerase II enzyme 3. creates iron-mediated free oxygen radicals that damage the DNA and cell membranes CAVE cardiotoxicity cumulative dose!!! Streptomyces Doxorubicin, Epirubicin BC, OC, hematologic mlg, lung ca Intercalation Doxorubicin Streptomyces

34 Crosslinking of DNA (CCNS cell cycle non specific antineoplasmatic agents) Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplasmatic agents) Platin based alkylating like agents cisplatin, karboplatin, oxaliplatin Nonclasical dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, CDK, PI, PARP

35 Alkylating antineoplastic agent attaches an alkyl group (CnH2n+1) to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring similar to mustard gas Cyklofosfamid - potent immunosuppressive substance - hematologic mlg.,testicular tu, - sarcoma, lung ca

36 Platinum-based agents platinum complexes react in vivo, binding to and causing crosslinking of DNA which ultimately triggers apoptosis CDDP(cisplatina) nefrotoxicity, resistence Oxaliplatina CBDCA (karboplatina) - myelosuppresive platin based combination chemotherapy is the cornerstone of treatment of many cancers E.g. sarcomas, Ca, lymfomas, gemcell tumors

37 Nonclassical alkylating agents Dacarbazine (DTIC) malignant melanoma, HD, sarcoma Temozolomid glioblastoma multiforme (G IV strocytoma)

38 Alkylation + intercalation Bleomycin - glycopeptid ATB - produced by Streptomycetes - HD, testicular tumors Mitomycin - Produced by Streptomycetes - BC, bladder Ca.,

39 Enzyme inhibitors Inhibition of mitosis (M phase) Inhibition of microtubules polymerization Hyperstabilisation of microtubules Antifolates vinca alkaloids (vinkristin, vinblastin, vinorelbine) taxanes (paclitaxel, docetaxel) metotrexat, pemetrexed DNA precursors antimetabolites (S phase) Purin analogues Pyrimidin analogues mercaptopurine fluorouracil, capecitabine, gemcitabine Deoxiribonukleotides hydroxyurea Inhibition of DNA replication Isomerase's inhibitors (S phase) T I. inhibitors T II. inhibitors TII inh. + intercalators Alkylating agents topotecane, irinotecane etoposide antracyklins (doxorubicine, epirubicine) cyklofosfamide Crosslinking of DNA (cell cycle non specific antineoplasmatic agents) Platin based alkylating like agents cisplatin, karboplatin, oxaliplatin Nonclasical dacarbazine, temozolomide Others Enzyme inhibitors Intercalators bleyomycine FI, FI, CDK, PI, PI, PARP

40 farnesyltransferase inhibitor Ras undergoes through four steps of modification. One of them is isoprenylation that involves the enzyme farnesyltransferase (FTase) transferring a farnesyl group from farnesyl pyrophosphate (FPP) to the pre-ras protein. Also, a related enzyme geranylgeranyltransferase I (GGTase I) has the same ability (only for K and N-Ras) farnesyl is necessary to attach Ras to the cell membrane and without attachment to the cell membrane, Ras is not able to transfer signals from membrane receptors when FTase is blocked GGTase can fill in the modification => blocks only of FTase effect ) => blocks of both FTase and GGTase = toxicity recently in clinical trials Tipifarnib in development Ras P GDP P SH2 doména P Sos Grb Ras GDP Palmitoyltransferáza Farnesyltransferáza Ras GDP

41 cyclin-dependent kinase inhibitor Seliciclib preferentially inhibits multiple enzyme targets including CDK2, CDK7 and CDK9 which alter the growth phase or state within the cell cycle of treated cells has been found to produce apoptosis in treated cancerous cells of NSCLC - recently in clinical trials

Proteasome inhibitor Bortezomib - 1st proteasome inhibitor tested - inhibits its chymotrypsin-like proteolytic activity - proteasome inhibition may prevent

42 Proteasome inhibitor Bortezomib - 1st proteasome inhibitor tested - inhibits its chymotrypsin-like proteolytic activity - proteasome inhibition may prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells - in US approved for MM and mantle cell lymfoma Bortezomib

43 PARP inhibitors - Poly ADP Ribose Polymerase is a protein involved in repair of single or double- strand DNA breaks and programmed cell death - PARP inhibitors seem to be more succesful on cancer cells that are more dependent on PARP than normal cells => BRCA 1/2 mutated cells Olaparib - acts against cancer in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast and prostate cancers Olaparib

44 unclassified antineoplasmatic agents Trabectidin - derived from sea squirt - approved in EU for treatment of advanced soft tissue sarcoma - mechanism of action is believed to involve the production of superoxide near the DNA strand resulting in DNA backbone cleavage and cell apoptosis

45 Unclassified antineoplasmatic agents Tensirolimus - is an intravenous drug for the treatment of RCC - is a specific inhibitor of mtor (mammalian target of rapamycin) and interferes with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells - when the kinase activity of mtor is activated, its downstream effectors, the synthesis of cell cycle proteins such as cyclin D and hypoxia-inducible factor-1a are increased. HIF-1a then stimulates VEGF (Vascular endothelial growth factor) Oblimersen - blc2 antisense oligonukleotid - may act by blocking the production of anti apoptotic Bcl-2 protein and make them more sensitive to chemotherapy - studied for use in CLL, B cell lymphoma, BC

46 Immunotherapy Cancer immunotherapy attempts to stimulate the immune system to reject and destroy tumors by: 1) system administration of cytokines interferon α cytostatic and -lytic effect, variation of surface molecules imunogenicity - used RCC, hematoonkology interleukin 2 - activation of T lymphocytes - used: RCC, melanoma 2) BCG immunotherapy for early stage (non-invasive) bladder cancer utilizes instillation of attenuated live bacteria into the bladder, and is effective in preventing recurrence in up to 60 % of cases 3) adoptive immunoterapy e.g. administration of donor s Lymphocytes clinical research: melanoma 4) monoclonal Ig targeted terapy

2. Mitotic Spindle Inhibitors (modulators of tubulin polymerisation) 3. Antimetabolites (anti-folates, pyrimidine and purine analogues)

CANCER DRUG CLASSES The classes of drugs currently used in the cancer clinic are 1. DNA Binding Agents (intercalating and alkylating agents) 2. Mitotic Spindle Inhibitors (modulators of tubulin polymerisation)