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
CI-937,
CI-941 and
CI-942. In each case the dose-limiting toxicity was
leukopenia with other toxicities being minor.
CI-941 has shown significant activity in patients with advanced
breast cancer and these agents appear to have a bright future.