Von Hoff D D
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.
Semin Oncol. 1998 Aug;25(4 Suppl 10):31-6.
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.
右丙亚胺（DEX；ICRF - 187；Zinecard，法玛西亚普强公司，密歇根州卡拉马祖）的临床开发最初是将其作为一种抗肿瘤药物开始的。它在多种体外和体内模型中具有独特的作用机制和活性。该药物的Ⅰ期试验于1979年1月开始。Ⅰ期试验表明，DEX可以安全给药，白细胞减少和血小板减少是多种不同给药方案中的剂量限制性毒性反应。同时也观察到了一些抗肿瘤活性的迹象。在Ⅰ期研究中还发现，基于DEX的螯合能力，接受该药物的患者尿液中铁和锌的清除率显著增加。这一信息，再加上临床前研究中得出的DEX可以预防蒽环类药物引起的心脏毒性（通过减少自由基形成）的信息，促使DEX被用作心脏保护剂（本增刊中有详细讨论）。然而，除了作为心脏保护剂外，DEX还有其他潜在应用，概述如下，包括：（1）基于其作为血管生成抑制剂的活性，用于治疗获得性免疫缺陷综合征相关的卡波西肉瘤患者；（2）基于其增强顺铂对人卵巢癌细胞抗增殖作用的能力，增强顺铂的疗效；（3）用于治疗对去铁胺过敏的患者的铁过载状态；（4）治疗银屑病患者；（5）预防高氧对肺部的影响；（6）预防博来霉素诱导的肺纤维化；（7）减轻对乙酰氨基酚诱导的肝毒性；（8）预防粘膜炎；以及（9）其他应用。显然，应该进行更多的研究，以最大限度地发挥非常有趣的DEX分子的效用。
