UNIVERSITY OF LUSAKA CANCER CHEMOTHERAPY

Principles of cancer chemotherapy the ultimate goal of cancer treatment is cure cure requires complete eradication of tumor cells if cure is not attainable, the goal is palliation (alleviation of symptoms and avoidance of life threatening toxicity) drug therapy is a balance between toxic effects of drugs and their efficacy combination therapy is more efficacious than single dug therapy in most cancers for which chemotherapy is effective

Principles of cancer chemotherapy… In combination therapy, agents with qualitatively different toxicities and different molecular sites and mechanisms of action are usually combined at full doses; while those with similar dose limiting toxicities can be combined safely only by reducing the doses of each

Principles of cancer chemotherapy… Advantages of combination Provide maximum cell kill within the range of tolerated toxicity May slow or prevent the development of drug resistance

Problems associated with cancer chemotherapy Resistance Some neoplastic cells are inherently resistant to most anticancer dugs (e.g. melanoma) some tumors acquire resistance to the cytotoxic effects of the drugs particularly after prolonged administration of low doses the development of drug resistance is minimized by short term intensive intermittent therapy with combination of drugs

Problems associated with cancer chemotherapy… Mechanism of resistance over-expression of genes for target proteins drug inactivation by tumor cells defective apoptosis (programmed cell death) in tumor cells loss of receptors for hormonal anti-cancer agents One of the best characterized mechanisms is over-expression of the MDR-1 gene which codes for a cell membrane transporter that causes efflux of certain drugs (e.g. vinca alkaloids, taxanes, anthracyclines)

Problems associated with cancer chemotherapy… Toxicity The ideal chemotherapeutic drug would target and destroy only cancer cells, unfortunately, few such drugs exist therapy aimed at killing rapidly proliferating cancer cells also effects normal cells undergoing rapid proliferation e.g. buccal mucosa, GIT mucosa, hair follicles, sperm forming cells, bone marrow,

Problems associated with cancer chemotherapy… Common adverse effects include: Bone marrow suppression GIT injury (stomatitis, diarrhoea) fetotoxicity alopecia sterility carcinogenesis hyperuricaemia (due to DNA breakdown following cell death) localized tissue injury nausea and vomiting

Classes of Anti-cancer drugs Anti-metabolites Mitotic inhibitors DNA cross-linking drugs and alkylating agents Topo-isomerase inhibitors Platinum complexes Hormones Miscellaneous

Anti-metabolites Folate antagonist methotrexate- a folic acid analogue Inhibits dihydrofolate reductase and interferes with thymidylate synthesis commonly responsive tumors: choriocarcinoma, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, ovarian cancer, osteogenic sarcoma, head and neck cancer

Anti-metabolites… Methotrexate Toxicity: mucosal ulceration, bone marrow suppression, nausea and vomiting, renal damage, Toxicity can be reduced by giving folinic acid (tetrahydrofolate) increased toxicity with impaired renal function

Anti-metabolites… 2. Purine antagonist 6-mercaptopurine (a purine analogue) Blocks de novo purine synthesis uses: acute leukemia Toxicity: mutagenic, myelosuppression, immunosuppression b) Thioguanine (a purine analogue) Uses: leukemias Toxicity: myelosuppression, immunosuppression, hepatotoxic, nausea/vomiting, diarrhea

Anti-metabolites… 3. Pyrimidine antagonists 5-fluoro-uracil Inhibits thymidylate synthetase, therefore, inhibits DNA synthesis uses: GI tumor, breast cancer toxicity: mucositis, alopecia, myelosuppression, diarrhoea, nausea and vomiting, neurotoxicity

Anti-metabolites… b) Cytarabine Inhibits DNA synthesis by chain termination when incorporated into DNA uses: acute leukemia, lymphomas toxicity: myelosuppression, nausea/vomiting, stomatitis, hepatotoxic, skin rash, cerebella and conjunctival toxicities at high doses,

Anti-metabolites… c) Gemcitabine Chain termination when incorporated into DNA, therefore, inhibits DNA synthesis uses: pancreatic, lung and bladder cancer toxicity: myelosuppression, haemolytic-uremic syndrome

Anti-metabolites… 4. Ribonucleotide reductase inhibitor Hydroxyurea Inhibits conversion of ribonucleotides to deoxyribonucleotides, therefore, inhibits DNA replication Uses: chronic myeloid leukaemia, ovarian carcinoma, melanoma Toxicity: myelosuppression, renal impairment, neurotoxic, stomatitis, nauesa and vomiting

Mitotic inhibitors Vinca alkaloids -MoA: arrest mitosis by inhibiting polymerization of microtubules Vincristine - uses: lymphomas and acute leukaemias - toxicity: peripheral neuropathy, alopecia, irritant to tissue

Mitotic inhibitors… b) Vinblasine - uses: lymphomas, leukaemias, breast cancer, testicular cancer, Euring’s sarcoma, kaposis sarcoma toxicity: peripheral neuropathy, alopecia, myelosuppression, local tissue injury c) Vinorelbine uses: lung and breast cancer toxicity: peripheral neuropathy, myelosuppression

Mitotic inhibitors… 2. Taxanes MoA: promote assembly of microtubules- the overly stable microtubules formed are dysfunctional, thereby causing the death of the cell Paclitaxel (taxol) uses: breast, lung, ovarian, head and neck, and bladder cancer Toxicty: myelosuppression, alopecia, arthralgia, neuropathy

DNA cross-linking drugs and alkylating agents MoA: form adducts with DNA causing DNA strand breaks Nitrogen mustard, chlorambucil, cyclophosphamide, nelphalan, ifosfamide Alkylating agents –transfer an alkyl group to DNA uses: Hodgkins disease, lymphomas, small cell lung cancer, breast and testicular cancer, chronic lymphocytic leukemia, multiple myeloma, malignant gliomas Toxicity: alopecia, leukemogenic, aspermia, permanent sterility, hemorrhagic cystitis ( with cyclophophamide and ifosfamide)

DNA cross-linking drugs and alkylating agents…. b) Procarbazine Causes chromosomal damage and suppress synthesis of DNA and RNA uses: hodgkin’s disease Toxicity: myelosuppression, nausea and vomiting, neurotoxic, secondary leukaemias

Topo-isomerase inhibitors Anthracyclines MoA: inhibit topo-isomerase II and cause DNA strand breaks through intercalation with DNA Doxorubicin uses: acute leukemia, lymphoma, breast and lung cancer toxicity: nausea/vomiting, myelosuppression, alopecia, cardiotoxicity Daunorubicin use: acute leukemias toxicity: as doxorubicin

Topo-isomerase inhibitors… b) Podophyllotoxins Etoposide MoA: inhibit topo-isomerase II and cause DNA strand breaks uses: lymphomas, testicular cancer, lung cancer (especially small cell) acute leukemia toxicity: nausea vomiting, myelosuppression, neutropenia, peripheral neuropathy

Topo-isomerase inhibitors… c) Camptothecins Topotecan Inhibits topo-isomerase I and II resulting in DNA damage uses: ovarian and small cell lung cancer toxicity: myelosuppression

Platinum complexes MoA: establish cross-links within and between DNA strands and inhibit DNA synthesis and function Cisplatin uses: lung cancer, testcular, breast and ovarian cancer toxicity: severe persistent vomiting, nephrotoxic, decrease Mg++, decrease Ca++, ototoxic, neurotoxic, anaemia, myelosuppression b) Carboplastin uses: lung, head and neck, ovarian and breast cancer toxicity: myelosuppression, peripheral neuropathy.

Hormones Tamoxifen MoA: oestrogen receptor antagonist Uses: oestrogen dependent breast cancer Toxicity: hot flushes, hypercalcaemia, deep venous thrombosis b) Diethylstibestrol An oestrogen- inhibits the growth of prostatic tissue by blocking the production of luteinizing hormone thereby decreasing synthesis of androgens Use: prostate cancer Adverse effects: gynaecomastia, impotence, thrombo-embolism

Hormones… c) Flutamide Androgen receptor blocker use: prostate cancer adverse effects: decrease libido, hot flushes, gynaecomastia d) Leuprolide acetate Inhibits gonadotropin secretion adverse effects: hot flushes, decreased libido

Hormones… e) Anastrozole Aromatase inhibitor: blocks conversion of androgen to oestrogen breast cancer adverse effects: osteoporosis, hot flushes f) Megestrol acetate Progestrone agonist breast and endometrial cancer adverse effects: weight gain, fluid retention

Hormones… g) Prednisolone Toxic to lymhoid tissue use: acute lymphocytic leukemia, lymphomas adverse effects: fluid retention, hypertension, diabetes, increased susceptibility to infection, moon face

Miscellaneous nitrosoureas-carmustine and lomustine Alkylate DNA use: brain tumor, lymphoma (carmustine) toxicity: myelosuppression, pulmonary toxicity, nephrotoxic b) Imatinib Inhibits tyrosine kinase use: chronic myeloid leukaemia, GI stremal tumors toxicity: leukopenia, hepatotoxic, oedema

Miscellaneous… c) Bleomycin Causes DNA strand breaks use: squamous cell carcinoma, lymphoma, testicular cancer toxicity: anaphylaxis, chills and fever, pulmonary fibrosis d) Mitomycin Alkylates DNA use: gastric adenocarcinoma; colon, breast and lung cancer, transitional cell cancer of the bladder toxicity: local extravation causes tissue necrosis, myelosuppression, fever, leukopaenia, throbocytopaenia, alopecia, haemolytic- uremic syndrome

Miscellaneous… e) Interferon-alpha anti-proliferative effect use: hairy cell leukemia, chronic myeloid leukemia, Kaposi's sarcoma(AIDS), renal cell cancer, melanoma toxicity: fatigue, fever, myalgias, arthralgias, myelosuppression, nephrotic syndrome (rare)

Miscellaneous… f) Asparaginase An enzyme that depletes asparagine, on which leukemic cells depend (they have limited capacity to make L-asparagine) use: acute lymphocytic leukemia Toxicity: acute anaphylaxis, hyperthermia, pancreatitis, hyperglycemia, hypofibrinogenemia, seizures, coma, liver dysfunction

Miscellaneous… g) Rituximab (a monoclonal antibody) Binds to CD 20 on B-cells use: B-cell lymphoma toxicity: hypersensitivity reactions h) Actinomycin-D (Dactinomycin) Intercalates with DNA thereby inhibiting RNA synthesis wilm’s tumor, rhbdomyosarcoma, Euring’s sarcoma, kaposi’s sarcoma, choriocarcinoma Toxicity: corrosive to tissue, stomatitis, nausea/vomiting, myelosuppression