MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS

1997年底至1998年初，一种新的三核铂化合物BBR 3464， 将进入第一阶段临床试验，第一个真正的新铂 不基于经典顺铂结构的试剂来这样做。 的 临床前活性特征反映了其独特的结构， 以在人肿瘤（如卵巢）异种移植物中的活性为特征的 耐顺铂和烷化剂;在广泛的 通常对化疗不敏感的人类肿瘤谱 干预（例如，非小细胞肺、胃），特征为 p53突变体。 p53蛋白被认为是在 对药物诱导的DNA损伤的细胞反应。 正常p53缺失 功能降低可导致内在耐药性， 细胞参与凋亡反应的能力。 因此，临床药物 独立于p53通路发挥作用， 化疗有望在超过50%的人类实体肿瘤中发挥作用， 缺陷型p53。 这一提议将探讨这些新的假设， 与其他临床药物相比， 和抗肿瘤活性，在p53-非依赖性的方式，通过差异 修复可追溯到一系列独特的DNA加合物， 并影响目前在治疗中使用的任何DNA损伤剂。 诊所 因此，本建议将描述加合物的类型 形成并开始检查其结构后果， 蛋白质识别和DNA修复。

In late 1997 - early 1998 a novel trinuclear platinum compound, BBR3464, will enter Phase 1 clinical trials, the first genuinely new platinum agent not based on the classical cisplatin structure to do so. The profile of preclinical activity mirrors its unique structure and is characterized by activity in human tumor (e.g. ovarian) xenografts resistant to cisplatin and alkylating agents; a high activity in a broad spectrum of human tumors commonly insensitive to chemotherapeutic intervention (e.g. non-small-cell lung, gastric) and characterized as p53-mutant. The p53 protein is recognized as playing a critical role in cellular response to drug-induced DNA damage. Loss of normal p53 function can lead to intrinsic drug resistance as a result of reduced cell ability to engage an apoptotic response. Thus, a clinical drug acting independently of the p53 pathway can offer outstanding clinical promise for chemotherapy in over 50 percent of solid human tumors with defective p53. This proposal will explore the hypothesis that these new agents, in comparison to other clinical agents, exert their cytotoxicity and antitumor activity in a p53-independent manner through differential repair traceable to a unique array of DNA adducts, different in scope and effect to any of the DNA-damaging currently agents used in the clinic. This proposal will therefore delineate the types of adducts formed and begin to examine the structural consequences thereof with respect to protein recognition and DNA repair.