DEVELOPMENT OF MITOTANE ANALOGS FOR ADRENAL CANCER

治疗肾上腺癌的米托坦类似物的开发

• 批准号: 3175624
• 负责人: DAVID Eduardo SCHTEINGART
• 金额: $ 18.34万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-08-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3175624
• 关键词: Cushing's syndrome; adrenal neoplasm; adrenocorticotropic hormone; antineoplastics; carcinoma; cytochrome P450; dogs; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; halocarbon compound; methyl group; methylene chloride; pharmacokinetics

Mitotane (o,p'-DDD) is an adrenalytic drug used in the treatment of adrenal cancer and benign Cushing's syndrome. When given in effective doses, its use is limited by toxicity. The aim of this investigation is to develop more effective protocols for the administration of Mitotane and Mitotane analogs which should yield greater adrenalytic effects and decreased toxicity. Based on our previous studies with Mitotane and Mitometh and reports on the activation metabolism of p,p'-DDD and other halogenated hydrocarbons, we postulate that the adrenalytic action of Mitotane is linked to the ability of the dichloromethyl group to become metabolically oxidized to an activated electrophylic species, an acyl chloride, which covalently binds to metabolically important macromolecules in the adrenal cortex. We plan to study this mechanism further using a dog model in which the adrenalytic effect will be assessed by suppression of cortisol and increase in ACTH levels, adrenal response to ACTH stimulation, histological evidence of adrenal necrosis and in vitro suppression of transformation of radiolabeled Mitotane to DDA. We will determine if the administration of cytochrome P-450 enzyme mitochondrial inhibitors can block Mitotane effects by suppressing its metabolism and if the administration of P-450 inducers can enhance the adrenalytic effects of the drug. We will determine by autoradiographic morphological studies the cellular site(s) of Mitotane metabolism and action. In order to increase activity of Mitotane, we plan to synthesize bromochloro and bromofluoro analogs. These substitutions may render compounds which are more cytotoxic to the adrenal. Another goal of the study is to ascertain ways in which toxicity of Mitotane may be ameliorated. Toxicity will be evaluated in the dog by assessing changes in serum cholesterol, SGOT, SGPT, alkaline phosphatase and histological evidence of hepatic necrosis. We plan to determine if there are differences in metabolic pathways in adrenal as compared to liver in regards to the effects of Mitotane and its analogs and to investigate the role of glutathione in the bioactivation or detoxification of Mitotane metabolites. Assuming that the toxicity of Mitotane may be due, in part, to its high lipophilicity and poor absorption, we plan to synthesize Mitotane analogs in which one or both of the aromatic chlorines is replaced with amino groups. By these changes, we may obtain a better balance between lipophilicity and hydrophilicity in order to improve absorption and adrenal bioavailability. If enzyme inducers are able to enhance the activity of Mitotane in the adrenal without added toxicity and if the new Mitotane analogs appear to have a more favorable therapeutic index, we plan to carry out a pilot study in which these compounds will be used in dogs with Cushing's disease and adrenal cancer. We also plan to determine if it is possible to predict the response to therapy by measuring metabolic activity in vitro using incubation of adrenal tumor homogenates.

Mitotane（O，P'-DDD）是一种用于治疗的肾上腺素分析药物 肾上腺癌和良性库欣综合症。 当有效时 剂量，其使用受到毒性的限制。 这项调查的目的是 开发更有效的Mitotane的协议 和拟烷类似物，应产生更大的肾上腺分析作用和 毒性降低。 基于我们以前对Mitotane和 mitometh并报告了P，P'-DDD和其他的激活代谢 卤代烃，我们假设 Mitotane与二氯甲基的能力有关 将代谢氧化为活化的电植物，酰基 氯化物，共价结合代谢上重要 肾上腺皮质中的大分子。 我们计划研究这种机制 进一步使用狗模型，在该模型中将是肾分析效应 通过抑制皮质醇和ACTH水平升高评估，肾上腺 对ACTH刺激的反应，肾上腺坏死的组织学证据 并在体外抑制放射性标记的Mitotane转化 DDA。 我们将确定施用细胞色素P-450酶 线粒体抑制剂可以通过抑制其阳性抑制 代谢以及P-450诱导剂的给药可以增强 该药物的肾分析作用。 我们将通过放射自显影确定 形态学研究Mitotane代谢和 行动。 为了增加Mitotane的活动，我们计划合成 Bromochloro和Bromofluoro类似物。 这些替代可能会导致 对肾上腺更细胞毒性的化合物。 该研究的另一个目标是确定如何在哪种毒性 乙烷可能会得到改善。 毒性将在狗中评估 评估血清胆固醇，SGOT，SGPT，碱性磷酸酶的变化 和肝坏死的组织学证据。 我们计划确定是否 与 肝脏及其类似物的影响以及 研究谷胱甘肽在生物活化或 米托烷代谢产物的解毒。 假设毒性的毒性 米托烷可能部分归因于其高亲脂性和差 吸收，我们计划合成一个或两者的米托烷类似物 芳族氯的含量被氨基群代替。 通过这些 变化，我们可以在亲脂性和 亲水性以改善吸收和肾上腺 生物利用度。 如果酶诱导剂能够增强Mitotane的活性 肾上腺没有添加毒性，如果新的Mitotane类似物似乎 有一个更有利的治疗指数，我们计划执行飞行员 研究这些化合物将用于库欣的狗 疾病和肾上腺癌。 我们还计划确定是否可能 通过测量代谢活性来预测治疗的反应 使用肾上腺肿瘤匀浆的孵育。