BIOCHEMICAL STRATEGIES TO INCREASE LEUKEMIA RESPONSE

提高白血病反应的生化策略

• 批准号: 2098363
• 负责人: VARSHA GANDHI
• 金额: $ 12.26万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-15 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2098363
• 关键词: DNA damage; DNA directed DNA polymerase; acute myelogenous leukemia; antileukemic agent; combination cancer therapy; cytosine arabinoside; cytotoxicity; deoxyadenosines; deoxyuridine; drug detection; drug interactions; drug metabolism; drug screening /evaluation; flow cytometry; human subject; hydroxyurea; mitoxantrone; neoplasm /cancer pharmacology; tissue /cell culture

The central goal of this proposal is to develop hypotheses for optimized administration of drug combinations for the therapy of acute myelogenous leukemia (AML) based on in vitro pharmacological, biochemical, and molecular studies. Subsequently, protocols will be designed to evaluate the pharmacokinetic and pharmacodynamic predictions of these hypotheses and for clinical response. Because ara-C is important for the therapy of AML, attempts will be directed toward enhancing its efficacy by biochemical modulation strategies, dosing and scheduling, and by combination of other effective antileukemic drugs. Pilot studies conducted under R03 CA53311 have demonstrated that fludarabine infusion increased the rate of ara-CTP accumulation nearly 2-fold in leukemia blasts over that after ara-C alone in the same patient. Clinically, the combination of these two agents resulted in better response rates than our previous treatments. In the present proposal we plan to extend that work by investigating the mechanism of potentiation of ara-CTP metabolism by fludarabine and by studying the molecular action of these two analogue triphosphates to understand the synergistic cytotoxicity. We have amended the protocol based on the pharmacology studies and will investigate the cellular pharmacokinetics and pharmacodynamics to seek correlations with clinical response. Additionally, we will implement a new protocol: combination of ara-C and fludarabine with a DNA damaging agent, mitoxantrone. Pharmacokinetics of ara-CTP accumulation in leukemic blasts will be analyzed to evaluate the modulatory action of fludarabine and mitoxantrone. Studies will be performed to analyze the DNA damage introduced in vivo into unlabeled leukemia cells from patients receiving mitoxantrone therapy. Biochemical studies of the interaction of these agents for ara-CTP metabolism and for DNA damage in vitro in leukemic blasts isolated from the same patient will be conducted to complement and extend in vivo investigations. Correlations will be sought between these studies to determine the prognostic significance of modulation of ara-CTP metabolism. Knowledge gained from these investigations will be used to optimize scheduling of drugs for the existing protocol and to design and evaluate new treatments.

该提案的中心目标是提出优化假设 用于治疗急性骨髓性骨髓瘤的药物组合的施用 白血病（AML）基于体外药理学、生化和 分子研究。 随后，将设计协议来评估 这些假设的药代动力学和药效学预测 以及临床反应。 因为 ara-C 对于治疗很重要 AML，将尝试通过以下方式提高其功效 生化调节策略、剂量和时间安排，以及 联合其他有效的抗白血病药物。 R03 CA53311 下进行的试点研究表明 氟达拉滨输注几乎增加了ara-CTP积累率 相同情况下单独使用 ara-C 后，白血病原始细胞数增加 2 倍 病人。 临床上，这两种药物联合使用会产生 比我们以前的治疗有更好的反应率。 在现在 建议我们计划通过调查机制来扩展这项工作 氟达拉滨对 ara-CTP 代谢的增强作用并通过研究 这两种类似物三磷酸盐的分子作用，以了解 协同细胞毒性。 我们根据以下内容修改了协议 药理学研究并将研究细胞药代动力学 和药效学以寻求与临床反应的相关性。 此外，我们将实施一个新协议：ara-C 和 氟达拉滨与 DNA 损伤剂米托蒽醌。 药代动力学 将分析白血病细胞中 ara-CTP 的积累，以评估 氟达拉滨和米托蒽醌的调节作用。 研究将是 用于分析体内引入未标记的 DNA 损伤 来自接受米托蒽醌治疗的患者的白血病细胞。 生化 研究这些药物对 ara-CTP 代谢的相互作用以及 从同一患者分离出的白血病原始细胞中的 DNA 体外损伤 将进行补充和扩展体内研究。 将寻求这些研究之间的相关性以确定 ara-CTP 代谢调节的预后意义。 知识 从这些调查中获得的信息将用于优化调度 现有方案的药物以及设计和评估新的药物 治疗。