Combined Cancer Chemotherapy

Combined cancer chemotherapy

ALL Acute Lymphoblastic Leukemia (Childhood) Until chemotherapy – mean survival after diagnosis – 3m

First advance – methotrexate (folic acid antagonist – inhibitor of DHFA reductas

FADHFATHFA1C donor (e.g. folinic acid) thymidylate synthase/serine/methionine) Methotrexate Ki ~ 1uM, polyglutamate derivatives=prolonged action Resistance – e.g. decreased transport Solution – rescue therapy with folinic acid (leukovorin)

Present preferred therapy • • •

Initially MOPP – (leukemia) Meclorethamine (alkylator – myelosuppression) Oncovin (vincristine) – (M-phase specific/tubulin depolimrization – periferal neuropathies) • Prednisone – (Inhibition of lymphocyte proliferation – fluid retention, hypertension, diabetes, infection) • Procarbazine (Alkylator? – meyelosuppression, CNS) • • • •

Now Induction - Oncovine+prednisone Maintenance – mercaptopurine/MTX/cyclophosphamide Intrathecal MTX for treatment/prevention of brain metastases

• Median survival – 4 years

Hodgkin’s lymphoma • • • • • •

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Usually young people Untill late stages – confined to the lymphatic system Single node – intensive radiotherapy Initially MOPP (Response>80%) Now ABVDAdriamycin (doxorubicin) – (IntercalationDNA/RNA synthesis; Topoisomerase II inhibitionstrand scission; Semiquinone free radicals – general toxicity) – Irreversible/total dose-dependent cardiotoxicity (CoQ --?) Bleomycin-CCS G2 arrest – (Binding to DNA and free radical (Fe2+) generationstrand scission) – Anaphylaxis, pulmonary fibrosis – little myelosuppression Velban (Vinblastine) – As vincristine – more myelosuppression but less neurotoxcity Dacarbazine – (Alkylator via carbonium ion) -- myelosuppression

ABVD 80% complete remission from stage III & IV   >50% disease free for > 2 years   >40% cured!!! • • •

Alternative Lomustine (nirosourea alkylator -- myelsuppression) Mitoxantrone (DNA binding-strand scission) --Leukopenia