Hausheer F H, Kanter P, Cao S, Haridas K, Seetharamulu P, Reddy D, Petluru P, Zhao M, Murali D, Saxe J D, Yao S, Martinez N, Zukowski A, Rustum Y M
BioNumerik Pharmaceuticals, Inc, San Antonio, TX 78229, USA.
Semin Oncol. 1998 Oct;25(5):584-99.
Platinum-type drugs have proven to be valuable in the treatment of a variety of solid tumors, beginning with the commercial approval of cisplatin 18 years ago. There are several clinically important toxicities commonly associated with the administration of these drugs. Despite the extensive use of cisplatin and carboplatin, the fundamental chemical transformations and mechanisms that underlie their antitumor and toxic effects have not been fully characterized. Several first-generation protective thiols have been clinically studied in an attempt to reduce the toxicity of platinum-type drugs; while some of these agents appear to protect against certain toxicities, nearly all platinum-protecting drugs have their own intrinsic toxicities, which can be additive to the toxicity of platinum-type drugs. Tumor protection by platinum-protecting drugs is an additional untoward effect that is associated with certain types of agents and must be addressed with care. Recent advances in theoretical and laboratory methods and the use of supercomputers have extended our understanding of the possible major mechanisms underlying platinum drug antitumor activity and toxicity; we present strong evidence that there are two classes of chemical species of platinum drug. One class appears to predominantly account for the antitumor activity, and the other class of chemical species produces many of the toxic effects of platinum drugs. We have discovered a new nontoxic, second-generation platinum-protecting agent, known as BNP7787, which appears to selectively inactivate and eliminate toxic platinum species. BNP7787 has recently entered phase I clinical testing in cancer patients.
自18年前顺铂获得商业批准以来，铂类药物已被证明在多种实体瘤的治疗中具有重要价值。这些药物的使用通常会伴随几种临床上重要的毒性。尽管顺铂和卡铂被广泛使用，但其抗肿瘤和毒性作用背后的基本化学转化和机制尚未完全明确。几种第一代保护性硫醇已进行了临床研究，试图降低铂类药物的毒性；虽然其中一些药物似乎能预防某些毒性，但几乎所有的铂保护药物都有其自身的内在毒性，这些毒性可能会叠加铂类药物的毒性。铂保护药物对肿瘤的保护作用是与某些类型药物相关的另一种不良效应，必须谨慎对待。理论和实验室方法以及超级计算机的使用方面的最新进展，扩展了我们对铂类药物抗肿瘤活性和毒性潜在主要机制的理解；我们提供了有力证据，证明铂类药物存在两类化学物质。一类似乎主要负责抗肿瘤活性，另一类化学物质则产生铂类药物的许多毒性作用。我们发现了一种新的无毒第二代铂保护剂，称为BNP7787，它似乎能选择性地使有毒铂类物质失活并消除。BNP7787最近已进入癌症患者的I期临床试验。
