Phase I trials of dexrazoxane and other potential applications for the agent.
The clinical development of dexrazoxane (DEX; ICRF-187; Zinecard, Pharmacia and Upjohn, Kalamazoo, MI) was originally begun using it as an antineoplastic agent. It had a unique mechanism of action and activity in a variety of in vitro and in vivo models. Phase I trials with the agent began in January 1979. The phase I trials indicated that DEX could be safely administered, with leukopenia and thrombocytopenia being the dose-limiting toxicities, on a number of different schedules of administration. Some hints of antitumor activity were also noted. In the phase I studies it was also noted, based on the chelating abilities of DEX, that the compound caused marked increases in urine clearance of iron and zinc in patients receiving the agent. That information, plus the information being generated in preclinical studies that DEX could protect against the cardiotoxicity induced by anthracyclines (through a decrease in free radical formation), led to the use of DEX as a cardioprotective agent (as thoroughly discussed in this supplement). However, in addition to working as a cardioprotective agent, DEX has other potential applications that are outlined below and include (1) treatment of patients with acquired immunodeficiency syndrome-related Kaposi's sarcoma, based on its activity as an angiogenesis inhibitor; (2) enhancement of the effects of cisplatin, based on its ability to increase the antiproliferative effects of cisplatin on human ovarian cancer cells; (3) use for treatment of iron overload states in patients who are allergic to deferoxamine; (4) treatment of patients with psoriasis; (5) protection from hyperoxic effects on the lungs; (6) protection from bleomycin-induced pulmonary fibrosis; (7) attenuation of acetaminophen-induced hepatotoxicity; (8) prevention of mucositis; and (9) other applications. Clearly, there should be additional investigations to maximize the usefulness of the very interesting DEX molecule.
Von Hoff
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Institute for Drug Development, Cancer Therapy & Research Center, and the Department of Medicine, The University of Texas Health Science Center at San Antonio, 78245, USA.
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D002614:Chelating Agents / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D006801:Humans; D011929:Razoxane / Q000627:therapeutic use*; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D002317:Cardiovascular Agents; D002614:Chelating Agents; D059005:Topoisomerase II Inhibitors; D011929:Razoxane