Toward Improved Selectivity in Cancer Chemotherapy: The Richard and Hinda Rosenthal Foundation Award Lecture
Abstract
Approaches to improving the selectivity of drugs for the treatment of patients with cancer are discussed, with emphasis on folate antagonists as prototype compounds. The use of metabolites (leucovorin, 5-methyltetrahydrofolate) as "rescue" agents following methotrexate treatment with appropriate monitoring of blood levels of methotrexate has led to the safe use of this antimetabolite in high doses and an improved therapeutic index for the use of this drug in some human cancers. The use of methotrexate in conjunction with fluorouracil administration is sequence dependent in experimental tumor models and is being tested in human tumors. New folate antagonists, designed to inhibit thymidylate synthetase per se or as facilitators of 5-fluorodeoxyuridine 5'-monophosphate binding to this enzyme are also discussed. The potential for selectivity using nonclassical folate antagonists is also illustrated; in addition to Baker's antifol (triazinate), a triazine folate antagonist, now in clinical trial, several 2,4-diaminoquinazolines were found to be potent exhibitors of DNA synthesis in human leukemic leukocytes. Drug resistance to antineoplastic agents continues to be an important clinical problem. By using resistance to methotrexate as an example, exploitation of drug-resistant mutants by design of specific inhibitors is possible. A strategy for the prevention of drug resistance is advanced, based on data derived from experimental systems. It is concluded that large doses of drugs used in intermittent fashion and sequentially in combination may be the best strategy to avoid this problem. An example of this strategy is Adriamycin-cyclophosphamide-Oncovin-methotrexate-1-ß- D -arabinofuranosylcytosine, a five-drug sequential combination used to treat diffuse histiocytic lymphoma. 1 Presented at the 1978 Meeting of the American Association for Cancer Research in Washington, D. C. Supported in part by Grants CA08010 and CA08341 and Contract NO-1-CM-33711. 2 American Cancer Society Professor of Medicine and Pharmacology.