ANTHRAPYRAZOLES - TRUE SUCCESSORS TO THE ANTHRACYCLINES

The anthrapyrazoles are a new class of intercalating agents which were synthesized in order to reduce the potential for free radical generation and subsequent cardiotoxicity. Selected compounds showed a reduction in superoxide formation compared with doxorubicin plus inhibition of lipid peroxidation. Broad spectrum activity was seen against experimental tumors comparable with doxorubicin, with incomplete cross-resistance. The anthrapyrazoles bind to DNA, intercalate, preferentially inhibit DNA compared with RNA synthesis and form DNA single and double strand breaks consistent with inhibition of topoisomerase II. Clinical studies have been performed with Cl-937, Cl-941 and Cl-942. In each case the dose-limiting toxicity was leukopenia with other toxicities being minor. Cl-941 has shown significant activity in patients with advanced breast cancer and these agents appear to have a bright future.