Anti-cancers and their mechanism of action

An overview on Anti-cancers and their mechanism of action

1. ANTI-CANCERS AND THEIR MECHANISMS OF ACTION By; Dr Joyce MWATONOKA MMed PCH 1 st Year February 2019 Facilitator ; Prof E. Kamugisha Dr Mwatonoka Joyce 1

2. Outline Introduction Classification of anti-cancer drugs Anticancer drugs mechanisms of action - Alkylating agents - Antimetabolites - Cytotoxic antibiotics -Plant delivatives -Hormones -Monoclonal antibodies -Miscellaneous Dr Mwatonoka Joyce 2

3. Introduction Cancer is a disease characterized by uncontrolled multiplication and spread of abnormal forms of the body's own cells A normal cell turns into a cancer cell because of one or more mutations in its DNA, which can be acquired or inherited Dr Mwatonoka Joyce 3

4. Cont… Cancer arises as a result of a series of genetic and epigenetic changes, the main genetic lesions being: inactivation of tumor suppressor genes the activation of oncogenes (mutation of the normal genes controlling cell division and other processes). Dr Mwatonoka Joyce 4

5. Cont… Cancer cells characteristics that distinguish them from normal cells; Uncontrolled proliferation Dedifferentiation and loss of function Invasiveness Metastasis Dr Mwatonoka Joyce 5

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7. Normal Cell DNA Damage Mutations in the genome of somatic cells Alteration of genes that regulates apoptosis Expression of altered gene products Loss of regulatory gene product MALIGNANT NEOPLASM Activation of growth promoting oncogene Inactivation of cancer suppressor genes Acquired (environmental DNA damaging agents) Chemicals Radiation viruses Successful DNA repair Failure of DNA repair 8. CARCINOGENESIS Clonal expansion Additional mutations Heterogeneity Dr Mwatonoka Joyce 7

8. Cont… The cells compartments of solid solid tumors : Compartment A consists of dividing cells, possibly being continuously in cell cycle Compartment B consists of resting cells (G phase) which, although not dividing, are potentially able to do so Compartment C consists of cells that are no longer able to divide but which contribute to the tumour volume Dr Mwatonoka Joyce 8

9. Cont… O nly cells in compartment A, which may form as little as 5% of some solid tumors, are susceptible to the main current cytotoxic drugs which affect only one characteristic aspect of cancer cell biology- cell division In many cases, the antiproliferative action is during S phase of the cell cycle, and the resultant damage to DNA initiates apoptosis Dr Mwatonoka Joyce 9

10. Cont… Because most of anticancer drugs are antiproliferative , they also affect rapidly dividing normal cells and are thus likely to depress bone marrow, impair healing and depress growth Most cause nausea, vomiting, sterility, hair loss (reversible alopecia) and teratogenicity Dr Mwatonoka Joyce 10

11. Classification of anticancer drugs C ell cycle–specific (CCS) drugs; acts on proliferating cells, are most effective in hematologic malignancies and in solid tumors in which a relatively large proportion of the cells are proliferating C ell cycle–nonspecific (CCNS) drugs ; can kill both G and cycling cells (although cycling cells are more sensitive) . Are used in slow growing tumors Dr Mwatonoka Joyce 11

12. CCS drugs Vs CCNS drugs Dr Mwatonoka Joyce 12

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14. 1. Alkylating agents C ontain chemical groups that can form cross-bridge covalent bonds with DNA, as well as other nucleophilic substances in the cell Alkylating agents form a carbonium ion -a cation , which is highly reactive and react instantaneously with an electron donor ( nucleophile ) such as an amine, hydroxyl or sulfhydryl group Dr Mwatonoka Joyce 14

15. Cont… The major site of alkylation within DNA is the N7 position of guanine T o a lesser degree N1 and N3 of adenine , N3 of cytosine , and O6 of guanine, as well as phosphate atoms and proteins associated with DNA Eg ; cyclophosphamide Dr Mwatonoka Joyce 15

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18. 2. Antimetabolites These block or subvert one or more of the metabolic pathways involved in DNA synthesis a) Folate antagonists eg ; methotrexate Folates are essential for the synthesis of purine nucleotides and thymidylate , which in turn are essential for DNA synthesis and cell division Methotrexate inhibits dihydrofolate reductase Dr Mwatonoka Joyce 18

19. Cont… D ihydrofolate reductase converts the folate substrate ( polyglutamates ) first to dihydrofolate (FH 2 ), then to FH 4 FH 4 functions as an essential cofactor carrying the methyl groups necessary for the transformation of 2´-deoxyuridylate (DUMP) to the 2´-deoxythymidylate/ deoxythymidine monophosphate ( DTMP) required for the synthesis of purines and DNA Dr Mwatonoka Joyce 19

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22. Cont… b) Purine antagonists – e.g 6-mercaptopurine , inhibits several enzymes for purine biosynthesis. Also forms metabolites like 6-methylmercaptopurine ribotide (MMPR) which contribute to its cytotoxic action . Fludarabine in its trisphosphate form inhibits DNA polymerase c) Pyrimidine antagonist – eg 5-fluorouracil , also inhibit thymidylate synthetase hence inhibiting thymidilate synthesis - Cytarabine ; inhibits DNA polymerase Dr Mwatonoka Joyce 22

23. 3. Cytotoxic Antibiotics Is a widely used group of drugs that mainly produce their effects through direct action on DNA As a rule, they should not be given together with radiotherapy, as the cumulative burden of toxicity is very high Dr Mwatonoka Joyce 23

24. a) Doxorubicin DNA intercalation , Doxorubicin forms complexes with DNA through G bases in both of the DNA strands and prevents Topoisomerase II activity consequent in cell cycle disruption and cell death Topoisomerase II (a DNA gyrase ); relaxes DNA super coils by nicking to facilitate DNA replication/during RNA transcription Dr Mwatonoka Joyce 24

25. Cont… Dr Mwatonoka Joyce 25

26. b ) Dactinomycin Intercalates in the minor groove of DNA between adjacent guanosine -cytosine pairs, interfering with the movement of RNA polymerase along the gene and thus preventing transcription It affects mRNA and protein synthesis Also has an effect on topoisomerase II Dr Mwatonoka Joyce 26

27. c ) Bleomycins A re a group of metal-chelating glycopeptide antibiotics that degrade preformed DNA, DNA-Bleomycin-Fe +2 complexes undergo oxidation, the released electrons react with oxygen to form superoxide or hydroxyl radicals which attack phosphodiester bonds causing chain fragmentation and release of free bases Bleomycin is most effective in the G 2 phase, but it is also active against non-dividing cells Dr Mwatonoka Joyce 27

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29. 4. Plant derivatives ; a) Vinca Alkaloids Are derived from the Madagascar periwinkle The principal members are vincristine , vinblastine and vindesine The drugs bind to tubulin and inhibit its polymerisation into microtubules , preventing spindle formation in dividing cells and causing arrest at metaphase Their effects become manifest only during mitosis Dr Mwatonoka Joyce 29

30. Cont… Dr Mwatonoka Joyce 30

31. b) Taxanes Derived from the bark of the yew tree They bind on microtubules , stabilising them (in effect 'freezing' them) in the polymerised state, achieving a similar effect to that of the vinca alkaloids by arresting mitosis Dr Mwatonoka Joyce 31

32. 5. Hormones H ormone-dependent tumors have steroid receptors in the malignant cells Their growth can be inhibited by hormones with opposing actions, by hormone antagonists or by agents that inhibit the endogenous hormone synthesis Hormones or their analogues that have inhibitory actions on target tissues can be used in treatment Dr Mwatonoka Joyce 32

33. Cont… Such procedures alone rarely effect a cure but do mitigate the symptoms of the cancer Glucocorticoids such as prednisolone and dexamethasone have marked inhibitory effects on lymphocyte proliferation and are used in the treatment of leukaemias and lymphomas Dr Mwatonoka Joyce 33

34. Cont… Oestrogen ; Diethylstilbestrol and ethinyloestradiol used clinically in the palliative treatment of androgen-dependent prostatic tumours . However, they have been largely replaced by the GnRH analogues because of fewer adverse effects Estrogens inhibit the growth of prostatic tissue by blocking the production of LH in the pituitary gland, thereby decreasing the synthesis of androgens in the testis Dr Mwatonoka Joyce 34

35. Cont… Gonadotrophin -releasing hormone analogues ; inhibit gonadotrophin release. Used to treat advanced breast cancer in premenopausal women and prostate cancer. The transient surge of testosterone secretion that can occur in patients treated in this way for prostate cancer can be prevented by an antiandrogen such as cyproterone Dr Mwatonoka Joyce 35

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37. Hormone antagonists Antioestrogens eg ; tamoxifen competes with endogenous oestrogens for the oestrogen receptors and therefore blocking the proliferation actions of estrogen on mammary epithelium Antiandrogens , flutamide and bicalutamide , may be used either alone or in combination with other agents to treat tumours of the prostate. They are also used to control the 'flare' that is seen when treating patients with gonadorelin analogues Dr Mwatonoka Joyce 37

38. 6. Monoclonal antibodies Are immunoglobulins , of one molecular type, produced by hybridoma cells in culture, that react with defined target proteins expressed on cancer cells In some cases, binding of the antibody to its target activates the host's immune mechanisms and the cancer cell is killed by complement-mediated lysis or by killer cells Other attach to and inactivate growth factor receptors on cancer cells, thus inhibiting the survival pathway and promoting apoptosis Dr Mwatonoka Joyce 38

39. Cont… Rituximab used (in combination with other chemotherapeutic agents) for treatment of certain types of lymphoma . It lyses B lymphocytes by binding to the calcium channel-forming CD20 protein and activating complement. It also sensitises resistant cells to chemotherapeutic drugs Alemtuzumab is another monoclonal antibody that lyses B lymphocytes, and is used in the treatment of resistant CLL Dr Mwatonoka Joyce 39

40. 7. Miscellaneous agents Crisantaspase ; is a preparation of the enzyme asparaginase It breaks down asparagine to aspartic acid and ammonia, active against tumour cells that have lost the capacity to synthesize asparagine and therefore require an exogenous source, such as those of ALL The drug has a fairly selective action Dr Mwatonoka Joyce 40

41. References; 1. Rang and Dale’s Pharmacology 6E 2007. 2. Lippincott’s Illustrated Reviews - Pharmacology - 2nd Edition. Katzung Pharmacology Tenth Ed. Google images Dr Mwatonoka Joyce 41