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Chemotherapy drugs

Chemotherapy drugs. Emily Tyer. A quick run through the pathogenesis of cancer…. The Four characteristics of a cancer cell.. UNCONTROLLED PROLIFERATION DEDIFFERENTIATION AND LOSS OF FUNCTION INVASIVENESS METASTASIS. Normal cell. inheritance. i rradiation. viruses. carcinogens.

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Chemotherapy drugs

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  1. Chemotherapy drugs Emily Tyer

  2. A quick run through the pathogenesis of cancer…. • The Four characteristics of a cancer cell.. • UNCONTROLLED PROLIFERATION • DEDIFFERENTIATION AND LOSS OF FUNCTION • INVASIVENESS • METASTASIS

  3. Normal cell inheritance irradiation viruses carcinogens One or more mutation in its DNA Cancer cell

  4. Two main categories of genetic change • This is verrrry important! • Activation of proto-oncogenes  oncogenes • Inactivation of tumour suppressor genes

  5. PROTO-ONCOGENES • Control normal cell division, apoptosis and differentiation • Can be converted to oncogenes that induce malignant change TUMOUR SUPPRESSOR GENES • Normal cells contain genes that have the ability to suppress malignant change • Recessive in effect – need a two-hit process  both allele copies must be inactivated

  6. The CELL CYCLE Those cells never destined to divide e.g p53 G1, S, G2 = INTERPHASE

  7. Control of cell cycle • Cyclin-dependent protein kinases (Cdks) • Activation and deactivation at the appropriate time is crucial in the initiation and regulation of DNA replication, mitosis and cytokinesis • It is the responsibility of cellular proteins cyclins

  8. Anti-cancer drugs • Cytotoxic drugs • Alkylating agents • Antimetabolites • Cytotoxic antibiotics • Plant derivatives • Hormones • Mono-clonal antibodies • Protein kinase inhibitors • miscellaneous

  9. Cytotoxic drugs • Alkylating agents • Antimetabolites • Cytotoxic antibiotics • Plant derivatives S phase - replication Cross-linking Formation of a carbonium ion Highly reactive

  10. Nitrogenmustards • 1919 WW1 – mustard gas • First chemotherapy drug • released in 1946 - mustine • Cyclophosphamide • Inactive until P450 metabolism in the liver • Lymphocytes SE: nausea and vomiting Marrow depression Haemorrhagic cystis managed by mesna

  11. Cisplatin platinum compounds • Generate a reactive compound that cross-links between guanine units in DNA • Given by IV infusion – poor absorption from the gut • Excreted by kidney • SE: • PERIPHERAL NEUROPATHY • Nausea and vomiting • Nephrotoxicity with irreversible renal impairment • Hypomagnesmia • Ototoxicity with hearing loss and tinnitus

  12. Cytotoxic drugs • Alkylating agents • Antimetabolites • Cytotoxic antibiotics • Plant derivatives • Folate antagonists • Pyrimidine analogues • Purine analogues

  13. Folate antagonists • Interfere with the • thymidylate synthesis Cytotoxic drugs Methotrexate Usually given orally SE: depression of bone marrow, damage to epithelium in GIT, oral mucosa

  14. Methotrexate DHRF DHRF F(glu)n FH2(glu)n FH4(glu)n DUMP DTMP Thymidylate sythetase Fluorouracil

  15. Pyrimidne analogues Fluorouracil uracil analogue Also interferes with DTMP synthesis Inhibition of DNA but not RNA or protein synthesis SE: GI epithelial damage and myleotoxicity

  16. Pyrimidine analogues Cytarabine analogue o the naturally occurring Nucleoside 2’-deoxycytidine Inhibits DNA polymerase SE: bone marrow and GI tract Nausea and vomiting

  17. Recap  Antimetabolites • Folate antagonists • Pyrimidine analogues • Purine analogues

  18. Cytotoxic drugs • Alkylating agents • Antimetabolites • Cytotoxic antibiotics • Plant derivatives Direct action on DNA As a rule they should not be given Together with radiotherapy  Toxicity is very high

  19. Cytotoxic antibiotics • Doxorubicin and the anthracyclines Doxorubicin Binds to DNA and inhibits both DNA and RNA synthesis • Topoisomerase II inhibitor • DNA gyrase – relieves strain • while DNA is being unwound Generate highly reactive free radicals SE: cardio toxicity, dysrhythmias and heart failure

  20. Bleomycin • Metal-chelating glycopeptide antibiotics • Degrade DNA, causing chain fragmentation and release of free bases Most effective in the G2 phase of the cycle and mitosis Often used to treat germ line cancers SE: pulmonary fibrosis – 10% of patients

  21. Cytotoxic drugs • Alkylating agents • Antimetabolites • Cytotoxic antibiotics • Plant derivatives • Vinca alkaloids • Paclitaxel and docetaxel taxens • Camptothecins • Etoposide

  22. Plant derivates (heterogenous group) • Vinca alkaloids (Vinblastine, Vincristine) from periwinkle plant Vinca rosea • Taxanes (Paclitaxel= Taxol, docetaxel = Taxotere) from needles of Pacific Yew plant Taxus brevifolia • Epipodophyllotoxin (etoposide) from Podophyllum peltatum (India) • Camptothecins (topotecan, irinotecan) from Camptotheca acuminata (China)

  23. Hormones • Hormone antagonists can be effective in the treatment of several types of hormone-sensitive tumours Tamoxifen Tamoxifen competes with endogenous oestrogen Used in treatment of hormone receptor positive breast cancer Inhibits the transcription of oestrogen-responsive effects

  24. Metabolised by the liver – cytochrome p450 Side effects • Similar to those of the menopause • Acts as a oestrogen receptor agonist in the bone – inhibits osteoclasts  reduces osteoporosis • ? Agonist in the endometrium  increased risk of endometrial cancer

  25. Mono-clonal antibodies • Produced by hybridoma cells in culture, • react with defined target proteins expressed on cancer cells • Rituximab lymphoma • lyses B-lymphocytes by binding to CD20 protein and activating compliment • Herceptin (Trastuzumab)  25% breast cancer overexpress HER-2 • Binds to HER-2 receptor and results in down-signalling

  26. Quiz Cytotoxic agent Doxorubicin Cisplatin Azathioprine Dactinomycin Vincristine Fludarabine Bleomycin Cyclophophamide Paclitaxel Pentostatin Side effect Lung fibrosis Haemorrhagic cystitis Cardiomyopathy Myleosuppresion, liver fibrosis, oral mucositis Peripheral neuropathy Hypersensitivity, neurotoxicty, myleosuppression

  27. I think that might be enough for one day…See year 2 plenary on chemotherapy – can access through lumps and bumps study guide

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