Mechanistic Studies on New Platinum Clinical Agents

描述(申请人提供)：本申请建议研究由我们实验室出现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，构成了一类重要的新的抗癌药物。第一个临床化合物，目前命名为BBR3464，是一种三核、双功能DNA结合剂，总电荷为4+。BBR3464目前正处于癌症患者的第二阶段临床试验。I期试验显示了通常无法用顺铂治疗的癌症的明显反应模式(cis-DDP cis-[PTCL(2)(NH(3))(2)])，包括黑色素瘤、胰腺癌和肺癌的反应。目的复发性卵巢癌和非小细胞肺癌的II期疗效已得到证实。临床前研究表明，在BBR3464治疗后，p53突变肿瘤中的活性和对p53的诱导微乎其微。另一种药物是多胺桥联双核化合物，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比较双核和三核化合物。高正电荷，至少两个铂配位单元与DNA结合，以及这种DNA结合的后果是与顺铂范式以及所有其他DNA修饰抗癌剂显著的结构和机制背离。 该项目的长期目标是了解一种独特的DNA加合物形成模式如何导致不同的细胞信号或“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的抗肿瘤活性模式。这是该项目的另一个长期目标，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的背景下。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。 这项拟议的研究探索了不同的多核铂类中的各种结构-功能关系。具体目标建立在迄今取得的谅解的基础上。长程链间交联键的形成及其构象灵活性可能导致损伤的非局部化并代表修复的巨大挑战的假设将被检验。带电药物在DNA骨架上预结合的重要性将被阐明，以确定长距离链内和链间交联的性质和方向。将研究新的高亲和力DNA结合剂，以确定在没有共价结合的情况下，静电和氢键相互作用对DNA结构和功能的影响。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.