IMPROVING THE THERAUPEUTIC INDEX OF PLATINUM COMPLEXES

耐药性的产生是临床应用的主要障碍。 顺铂。为了实现进一步的抗肿瘤反应，高剂量水平 其固有的严重毒性成为一种必要的妥协。这个 这项资助计划的目标是研究选定的混合 胺配体与铂(II)和铂(IV)配合物配位 增加治疗指数，特别是通过绕过 顺铂诱导抗性，降低寄主毒性。这样的一种 这项工作将涉及广泛的细胞毒性、生化、 药理学和毒理学评估，我们认为 在评估这些化合物的临床潜力方面至关重要。 将合成含有混合胺配体的铂配合物， 并评价了它们对啮齿动物的细胞毒性和抗肿瘤效果 以及对顺铂耐药的人类细胞株。抗肿瘤活性将 也可以用二氨基环己烷(DACH)-硫代铂(II)-进行评估- 或缺乏DACH-羧基铂(II)抗性的细胞 对顺铂的交叉耐药。铂诱导的DNA链间和 将确定链内交叉连接以确定 混合胺配体，以调节这些关键病变的动力学。 同样重要的是对目标器官毒性的评估。 这些药物：特别是体内肾处理铂 复合体将与它们诱导的潜力相关联。 肾脏受损。这些药物的体外(即细胞)药代动力学 化合物将类似地与细胞毒性和生化相关 观察。 这些研究将确定混合胺基团的能力 调节抗肿瘤活性、毒性和生化光谱 铂络合物的药理作用。这些数据也将在 为可能的临床开发选择一种类似物。

Development of drug resistance is major drawback in the clinical use of cisplation. To achieve further antitumor response, a high dose level with its inherent severe toxicity becomes a necessary compromise. The goal of this grant proposal is to study the ability of selected mixed amine ligands coordinated to platinum (II) nd platinum (IV) complexes to increase the therapeutic index, specifically by circumventing cisplatin-induced resistance and reducing host toxicity. Such an undertaking will involve broad aspects of cytotoxic, biochemical, pharmacological, and toxicological evaluations, which we believe to be essential in assessing the clinical potential of these compounds. Platinum complexes bearing the mixed amine ligands will be synthesized, and their cytotoxicity and antitumor efficacy evaluated against rodent and human cell lines resistant to cisplatin. Antitumor activity will also be assessed against diaminocyclohexane (DACH)-sulfatoplatinum (II)- or DACH-carboxypthalatoplatinum (II) resistant cells which lack cross-resistance to cisplatin. Platinum induced DNA interstrand and intrastrand cross-links will be determined to ascertain the potential of mixed amine ligands to modulate the kinetics of these critical lesions. Equally important will be an evaluation of the target organ toxicity of these agents: In particular, in vivo renal handling of platinum complexes will be ssessed and correlated with their potential to induce renal damage. In vitro (i.e., cellular) pharmacokinetics of these compounds will be similarly correlated to cytotoxic and biochemical observations. These studies will ascertain the ability of mixed amine groups to modulate the spectrum of antitumor activity, toxicity and biochemical pharmacology of platinum complexes. The data will also be vital in selecting an analog for possible clinical development.