Mechanistic Studies on New Platinum Clinical Agents

描述（由申请人提供）：本申请提出研究由我们实验室产生的多核铂化合物形成的DNA加合物的独特方面以及这些新结构形成的生物学后果。 这些化合物，其中两个或三个铂配位单元以线性方式连接，构成一类重要的新型抗癌药物。 第一个临床化合物，目前命名为BBR 3464，是一种三核双功能DNA结合剂，总电荷为4+。 BBR 3464目前正在癌症患者中进行II期临床试验。 I期试验证明了顺铂（cis-DDP cis-[PtCl（2）（NH（3））（2）]）通常无法治疗的癌症的明确缓解模式，包括黑色素瘤、胰腺癌和肺癌的缓解。 II期客观缓解已在复发性卵巢癌和非小细胞肺癌中得到证实。 临床前研究表明，在BBR 3464治疗后，在p53突变型肿瘤中具有活性和对p53的最小诱导。 第二种药物是一种多胺桥接的双核化合物，将于2002年初进入第一阶段临床试验，从而可以在一般类别中对双核和三核化合物进行比较。 高正电荷、至少两个Pt配位单元与DNA结合的存在以及这种DNA结合的后果是与顺铂范例以及实际上所有其他DNA修饰抗癌剂的显著结构和机制偏离。 该项目的长期目标是了解DNA加合物形成的独特模式如何导致不同的细胞信号传导或“下游”效应，如蛋白质识别，以及这些事件是否可能导致真正的新抗肿瘤活性模式。 该项目的另一个长期目标是将这些化合物的细胞毒性作用置于导致细胞死亡的分子途径中。 阐明这类新型抗癌药物的作用机制将有助于设计出更好、更特异的癌症治疗药物。 拟议的研究探讨了各种多核铂类内的各种结构-功能关系。 具体目标建立在迄今为止所取得的谅解基础上。 长距离链间交联的形成及其构象灵活性可能导致病变的离域，并代表修复的艰巨挑战的假设将被检查。 将阐明在确定长距离链内和链间交联的性质和方向的DNA骨架上的带电药物的预关联的重要性。 新的，高亲和力的DNA结合剂将被研究，以确定静电和氢键相互作用对DNA结构和功能的影响，在没有共价结合。最后，将利用多核铂化合物的独特结构来研究与单链DNA结合的后果。

DESCRIPTION (provided by applicant): This application proposes to study the unique aspects of the DNA adducts formed by the polynuclear platinum compounds that have emerged from our laboratory and the biological consequences of formation of these novel structures. These compounds, where two or three platinum coordination units are linked in a linear fashion, comprise an important new class of anticancer drugs. The first clinical compound, currently denominated BBR3464, is a trinuclear, bifunctional DNA binding agent with an overall 4+ charge. BBR3464 is now in Phase II clinical trials in cancer patients. The Phase I trials demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin, (cis-DDP cis-[PtCl(2)(NH(3))(2)]) including responses in melanoma, pancreatic and lung cancer. Objective responses in Phase II have been verified in relapsed ovarian cancer and non-small cell lung cancer. Pre-clinical studies indicated activity in p53-mutant tumors and a minimal induction of p53 following BBR3464 treatment. A second drug, a polyamine-bridged dinuclear compound, will enter Phase I clinical trials in early 2002, and thus allows comparison between di- and trinuclear compounds within the general class. The high positive charge, the presence of at least two Pt coordination units binding to DNA and the consequences of such DNA binding are remarkable structural and mechanistic departures from the cisplatin paradigm, and indeed all other DNA-modifying anticancer agents. It is the long-term goal of this project to understand how a unique pattern of DNA adduct formation may result in different cellular signaling or "downstream" effects such as protein recognition and whether such events may be dictated to lead to a genuinely new pattern of antitumor activity. It is a further long-term goal of this project to place the cytotoxic effects of these compounds into the context of molecular pathways leading to cell death. Elucidating the mechanism of action of this new class of anticancer agents will lead to design of better, more specific drugs for treatment of cancer. The proposed research explores a variety of structure-function relationships within the diverse polynuclear platinum class. The specific aims build on the understanding gained to date. The hypothesis that formation of long-range interstrand crosslinks, and their conformational flexibility, may lead to delocalization of the lesion and represent formidable challenges to repair will be examined. The importance of pre-association of the charged drug on the DNA backbone in determining the nature and direction of long-range intra and interstrand crosslinks will be elucidated. New, high-affinity DNA-binding agents will be studied to determine the effect of electrostatic and hydrogen-bonding interactions on DNA structure and function, in the absence of covalent binding. Finally, the unique structure of polynuclear platinum compounds will be exploited to study consequences of binding to single-stranded DNA.