DEVELOPMENTAL CHEMOTHERAPY

发育期化疗

• 批准号: 6101346
• 负责人: DAVID R SPRIGGS
• 金额: $ 18.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2001-07-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6101346
• 关键词: anthracyclines; antileukemic agent; antineoplastic antibiotics; antineoplastics; carboxypeptidase; cis platinum compound; clinical trials; combination cancer therapy; drug administration routes; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; growth inhibitors; human subject; human therapy evaluation; injection /infusion; laboratory mouse; leucovorin; neoplasm /cancer chemotherapy; nuclear magnetic resonance spectroscopy; paclitaxel; pharmacokinetics; retinoids; tissue /cell culture; uracil nucleoside

The objectives listed for project 1 in the last grant submission have been successfully addressed during the most recent funding period. The following major accomplishments may be cited as a consequence of the activities of Project 1: (1) DIFFERENTIATION: Since the last grant submission, MSKCC has been a leading center of the development and rational application of all trans-retinoic acid therapy for the treatment of acute promyelocytic leukemia. Studies supported by this program included studies of the pharmacokinetics and metabolism of all trans retinoic acid, its toxicity and its efficacy in the treatment of acute promyelocytic leukemia. (2) DRUG MODULATION AND RESISTANCE: Clinical trials of idarubicin, liposomal doxorubicin and intra hepatic verapamil have been completed. Combination studies of Edatrexate and established chemotherapy agents are continuing. (3) NEW AGENT DEVELOPMENT: A variety of new agents have been tested including edatrexate, lometrexol, deoxyspergualin, topotecan and chloroquinoloxalone sulfonamide. In the next funding period, we will continue our early drug development studies, focused on Phase I and Pharmacology studies of putative differentiation agents, modulation studies and new combination studies. The purpose of project 1 will be to provide Phase I toxicity and pharmacology data on promising new approaches to chemotherapy which can then be applied in a disease specific manner in both projects 2 and 3. The Specific Aims will be 1) To determine the clinical toxicity and pharmacology of PUTATIVE DIFFERENTIATION INDUCING AGENTS, including a new retinoid LNG 1069, phenylbutyrate, and a new analog of hexamethylene bisacetamide. 2) To conduct a dose escalation study of lobaplatin, a chemotherapy agent which appears to be good candidate for HIGH DOSE THERAPY with growth factor and autologous stem cell support. 3) To determine the effect of RESISTANCE MODULATING AGENTS on the toxicity and pharmacology of established anticancer agents. The modulating agents to be studied include carboxypeptidase G2, and edatrexate leucovorin. 4) To conduct phase I / pharmacology studies of NEW AGENTS AND COMBINATIONS which appear to be synergistic in preclinical studies. These studies will include Phase I studies of the murine/human chimeric antibody HC225 with CDDP, desoxyspergualin and murine antibody cc49, and edatrexate with CDDP / taxol as well as an adaptive control study of 96 h taxol/cddp.

上次提交的赠款中列出的项目 1 的目标是 在最近的资助期内成功解决了这一问题。这 以下主要成就可被引用为 项目 1 的活动：(1) 差异化：自上次拨款以来 据提交，MSKCC 一直是开发和 合理应用全反式维A酸疗法进行治疗 急性早幼粒细胞白血病。该计划支持的研究 包括所有反式药物的药代动力学和代谢研究 视黄酸、其毒性及治疗急性重症肌无力的疗效 早幼粒细胞白血病。 (2) 药物调节和耐药性：临床 伊达比星、脂质体阿霉素和肝内维拉帕米的试验 已完成。 Edatrexate 和已建立的组合研究 化疗药物仍在继续。 (3)新剂开发：多种 已测试的新药物包括依达曲沙、洛美曲索、 脱氧精胍菌素、拓扑替康和氯喹诺酮磺酰胺。 在下一个资助期内，我们将继续进行早期药物开发 研究，重点是假定的第一阶段和药理学研究 分化剂、调节研究和新组合研究。 项目 1 的目的是提供第一阶段的毒性和 有希望的新化疗方法的药理学数据可以 然后在项目 2 和 3 中以特定疾病的方式应用。 具体目标是 1) 确定临床毒性和 推定的分化诱导剂的药理学，包括一种新的 类维生素A LNG 1069、苯基丁酸酯和新的六亚甲基类似物 双乙酰胺。 2) 进行洛铂的剂量递增研究， 化疗药物似乎是高剂量的良好候选者 使用生长因子和自体干细胞支持进行治疗。 3) 至 确定阻力调节剂对毒性的影响和 已确定的抗癌药物的药理学。调节剂为 研究的包括羧肽酶 G2 和依达曲沙亚叶酸。 4) 至 进行新药和组合的 I 期/药理学研究 这在临床前研究中似乎具有协同作用。这些研究将 包括鼠/人嵌合抗体 HC225 的 I 期研究 CDDP、脱氧精胍菌素和鼠抗体 cc49，以及依达曲沙与 CDDP /紫杉醇以及96小时紫杉醇/cddp的适应性控制研究。