IMPROVING THE THERAUPEUTIC INDEX OF PLATINUM COMPLEXES

耐药性的发展是临床使用中的主要缺点， 顺式 为了达到进一步的抗肿瘤反应，高剂量水平 与其固有的严重毒性成为一个必要的妥协。 的 这项拨款提案的目标是研究选定的混合 与铂（II）和铂（IV）络合物配位的胺配体， 增加治疗指数，特别是通过规避 顺铂诱导的抗性和降低宿主毒性。 这样的 研究将涉及细胞毒性，生物化学， 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。 将合成带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功效 和对顺铂有抗性的人细胞系。抗肿瘤活性将 还针对二氨基环己烷（DACH）-硫酸合铂（II）- 或DACH-羧基酞酸铂（II）抗性细胞， 对顺铂的交叉耐药。 铂诱导的DNA链间和 将确定链内交联，以确定 混合胺配体来调节这些关键病变的动力学。 同样重要的是评估靶器官毒性， 这些药物：特别是，体内肾脏处理铂 复合物将被评估，并与它们的潜在诱导 肾损伤体外（即，细胞）药代动力学 化合物将类似地与细胞毒性和生物化学相关， 意见。 这些研究将确定混合胺基团的能力， 调节抗肿瘤活性、毒性和生化谱 铂络合物的药理学 这些数据也将是至关重要的， 选择类似物用于可能的临床开发。

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.