BIOTRANSFORMATION STUDIES WITH ORMAPLATIN

奥马铂的生物转化研究

• 批准号: 2096542
• 负责人: STEPHEN G CHANEY
• 金额: $ 14.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2096542
• 关键词: biological response modifiers; biotransformation; cis platinum compound; drug adverse effect; drug metabolism; gastrointestinal absorption /transport; intracellular transport; laboratory mouse; laboratory rat; mass spectrometry; plasma; thiocarbamate; thiosulfate

Ormaplatin [tetrachloro(d,1-trans) 1,2-diaminocyclohexaneplatinum(IV)] (also known as tetraplatin) is a second generation platinum drug that has recently entered phase I clinical trials. We have characterized the biotransformation of ormaplatin in tissue culture medium, in L1210 cells, and in rat plasma (both in vitro and in vivo). We have also shown that both diethyldithiocarbonate (DDTC) and S-2(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) are effective at reducing ormaplatin toxicity in the Fischer-344 rat and have characterized the effects of DDTC on the plasma biotransformations or ormaplatin. We now propose the following: (1) We plan to determine the and therapeutic effectiveness of the major plasma biotransformation products. These data should allow one to optimize the therapeutic potential of ormaplatin by selecting protocols that maximize the therapeutically effective biotransformation products and minimize the toxic ones. (2) We plan to characterize the intracellular biotransformations of ormaplatin in various tissues (liver, kidney, spleen and intestine) of the rat. These studies should allow a better understanding of the tissue selective toxicity of ormaplatin and other platinum drugs. (3) We plan to determine the effects of DDTC and WR-2721 on the intracellular tissue biotransformations of ormaplatin. In the case of DDTC we also plan to quantitate its effectiveness at removing Pt-protein adducts and quenching PtDNA monoadducts in the same tissues. (4) We also plan to determine the effect of i.v. sodium thiosulfate on the toxicity of i.p. ormaplatin in the Fischer-344 rat and determine the effect of thiosulfate on the peritoneal, plasma and tissue biotranformations of ormaplatin under the same treatment conditions. These studies should improve our understanding of how these compounds reduce the toxicity of ormaplatin and related compounds such as cisplatin. These data might also allow the selection and/or design of modifiers which have improved selectivity for reducing the toxic side effects of platinum drugs without intefering with their therapeutic usefulness.

奥马铂 [四氯(d,1-反式) 1,2-二氨基环己烷铂(IV)] （也称为四铂）是第二代铂类药物， 近期已进入I期临床试验。 我们已经描述了 奥马铂在组织培养基中的生物转化，L1210 细胞和大鼠血浆（体外和体内）。 我们还有 结果表明，二乙基二硫代碳酸酯 (DDTC) 和 S-2(3-氨基丙氨基)乙基硫代磷酸 (WR-2721) 有效 降低 Fischer-344 大鼠中的奥马铂毒性 描述了 DDTC 对血浆生物转化的影响或 奥马铂。 我们现在提出以下建议： (1) 我们计划确定 主要血浆生物转化的效果和治疗效果 产品。这些数据应该可以帮助人们优化治疗方案 通过选择最大化奥马铂潜力的方案 治疗有效的生物转化产品并最大限度地减少 有毒的。 (2) 我们计划表征细胞内 奥马铂在各种组织（肝、肾、 大鼠的脾脏和肠道）。 这些研究应该能够更好地 了解奥马铂和其他药物的组织选择性毒性 铂类药物。 (3) 我们计划确定DDTC和WR-2721的效果 奥马铂的细胞内组织生物转化。 在 DDTC 的情况下，我们还计划量化其去除效果 同一组织中的 Pt 蛋白加合物和猝灭 PtDNA 单加合物。 (4) 我们还计划确定静脉注射的效果。硫代硫酸钠 腹腔注射的毒性Fischer-344 大鼠中的奥马铂并测定 硫代硫酸盐对腹膜、血浆和组织的影响 相同处理条件下奥马铂的生物转化。 这些研究应该提高我们对这些化合物如何 降低奥马铂和相关化合物的毒性，例如 顺铂。 这些数据还可以允许选择和/或设计 改进选择性以减少毒副作用的改性剂 铂类药物的作用而不干扰其治疗 用处。