L-DOPA ANALOGS AS NEW ANTITUMOR AGENTS

与天然存在的儿茶酚胺左旋多巴有关的邻苯二酚 和多巴胺已被证明是有效的抗肿瘤剂，在广泛的 实验肿瘤谱，包括B16黑色素瘤、C1300 神经母细胞瘤和L1210和P388淋巴细胞白血病。 先前 合成工作已经产生了两种类似物，3，4-二羟基苄胺和 N-乙酰基3，4-二羟基苄胺，其显著改善了 抗肿瘤活性，并能够产生长期的幸存者， 实验性白血病 我们现在建议进行一个合成程序 基于在研究期间开发的生物数据生成新化合物， 这一部分的初始部分。 的毒理学和药理学分析 药物代谢、药代动力学和宿主毒性应提供 为第三代智能手机的合理设计奠定了必要的基础。 具有增强的抗肿瘤活性的药剂。 毒理学数据也将开始 解决在考虑之前必须回答的问题 这些药物可能适用于人类的癌症问题。 生物化学研究集中在确定的网站， 这些试剂与DNA聚合酶和核糖核苷酸还原酶的作用， 主要的行动地点。 对其他每一种潜在的影响 酶靶--二氢叶酸还原酶、胸苷酸合成酶和dNMP 激酶-将使用纯化的酶制剂以及 在野生型和耐药突变体中的透化细胞。 基于 作用机制，抗肿瘤细胞的基础等令人感兴趣的问题 选择性，特别是在非黑色素瘤细胞中，将使用 肿瘤细胞和骨髓细胞的短期培养， L1210荷瘤小鼠。 希望它能让我们定量地 抗肿瘤选择性的基础，并可能显示出显着的 肿瘤细胞和正常细胞之间的代谢差异， 根本意义。 我们希望这种多方面的做法将 继续生成重要的生物数据， 应用于改进剂的合成，同时， 必要的数据，以确定这些代理人似乎是合理的 用于人类最终临床试验的持续发展。

Ortho-catechols related to the naturally-occurring catecholamines levodopa and dopamine have been shown to be potent antitumor agents in a broad spectrum of experimental tumors, including B16 melanoma, C1300 neuroblastoma, and L1210 and P388 lymphocytic leukemias. Previous synthetic work has produced two analogs, 3,4-dihydroxybenzylamine and N-acetyl 3,4-dihydroxybenzylamine, which have significantly improved antitumor activity and are capable of producing long-term survivors in the experimental leukemias. We now propose to conduct a synthetic program generating new compounds based on the biologic data developed during the initial portion of this grant. Toxicologic and pharmacologic analysis of drug metabolism, pharmacokinetics, and host toxicity should provide the necessary foundation for the rational design of a third generation of agents with enhanced antitumor activity. Toxicologic data will also begin to address the questions that must be answered prior to the consideration of these agents as potentially applicable to the cancer problem in man. Biochemical studies have focused upon the identification of the site of action of these agents with DNA polymerase and ribonucleotide reductase as the principal sites of action. Effects upon each of the other potential enzyme targets--dihydrofolate reductase, thymidylate synthetase, and dNMP kinase--will be examined using purified enzyme preparations as well as permeabilized cells in wild type and drug-resistant mutants. Based upon mechanism of action, the intriguing question of the basis of antitumor cell selectivity, especially in the non-melanoma cells, will be addressed using short-term cultures of tumor cells and bone marrow cells derived from L1210-bearing mice. Hopefully, it will enable us to examine quantitatively the basis of antitumor selectivity and possibly demonstrate a significant metabolic difference between tumor cells and normal cells that may be of fundamental significance. We intend that this multifaceted approach will continued to generate important biologic data which can be immediately applied to the synthesis of improved agents, and concurrently, accrue the necessary data to determine which of these agents appears to be justified for continued development towards ultimate clinical trial in man.