Antineoplastic activity of continuous exposure to dexrazoxane: potential new role as a novel topoisomerase II inhibitor.
Although originally developed as an antitumor agent in the 1970s, dexrazoxane (DEX) is currently used as a cardioprotective agent in combination with doxorubicin (DOX). Due to concerns about anthracycline-induced cardiotoxicity at higher cumulative doses, many investigators have chosen to administer DOX by prolonged infusion. Therefore, with the ultimate goal of combining infusional DEX and DOX, we performed a phase I study of intravenous DEX alone as a 96-hour infusion. Surprisingly, the maximum tolerated dose of DEX identified in this study was 10- to 15-fold lower than previously determined using different schedules of administration. Results of pharmacokinetic studies in support of the trial have found that steady-state DEX plasma concentrations in the range of 4 to 5 micromol/L can be achieved safely. Because previous experiments have explored the ability of DEX to inhibit the catalytic activity topoisomerase II at low micromolar concentrations and due to a lack of in vitro cytotoxicity data for long-term exposures, we performed further laboratory studies to provide a context for our pharmacokinetic findings. As a result of these correlative studies, we have found that prolonged exposures to DEX are cytotoxic to human leukemic cells at concentrations that are clinically achievable.
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
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D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D011929:Razoxane / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D002317:Cardiovascular Agents; D059005:Topoisomerase II Inhibitors; D011929:Razoxane; D004317:Doxorubicin