Novel chemotherapeutic agents in clinical development

Abstract

The development of new chemotherapeutic agents for cancer treatment is pursued with the hope of finding compounds with novel chemical characteristics, unique mechanisms of action, and with improved therapeutic indexes. Seven novel agents at different stages of clinical development have been selected for review. D1694 is a thymidylate synthase inhibitor that has intriguing preclinical activity. The anthrapyrazoles consist of three analogues that are undergoing phase II testing at present. One of these agents, CI-941, has been reported to have significant clinical activity in breast cancer. Lometrexol is an inhibitor of glycinamide ribonuclide transformylase, a critical enzyme in purine biosynthesis, that is undergoing phase II testing. Taxotere, a semisynthetic analogue of taxol that stabilizes microtubules, is currently undergoing phase I testing. Gemcitabine, a fluorinated analogue of deoxycytidine that can inhibit ribonucleotide reductase and be incorporated into DNA, is undergoing phase II testing. BMY-25067 is a mitomycin C analogue that is less myelosuppressive and more active than mitomycin C in preclinical models. Topotecan, a topoisomerase I inhibitor, has been shown to cause myelosuppression as the dose-limiting toxicity in phase I testing. Although each of these agents have some unique and novel characteristics that merit their clinical testing, these agents' long-range clinical role will depend on their efficacy in randomized phase III comparative trials.