L-DOPA ANALOGS AS NEW ANTITUMOR AGENTS

与天然儿茶酚胺类左旋多巴相关的邻儿茶酚 和多巴胺已经被证明是广泛的有效的抗肿瘤药物 实验肿瘤谱，包括B16黑色素瘤、C1300 神经母细胞瘤、L1210和P388淋巴细胞性白血病。上一首 合成工作已经产生了两个类似物，3，4-二羟基苯甲胺和 N-乙酰基3，4-二羟基苄胺，已显著改善 具有抗肿瘤活性，能够在体内产生长期存活 实验性白血病。我们现在提议进行一项综合计划 根据生物数据产生新的化合物 这笔赠款的初始部分。黄曲霉毒素的毒理和药理分析 药物代谢、药代动力学和宿主毒性应提供 为第三代汽车的合理设计奠定必要基础 具有增强抗肿瘤活性的药物。毒理学数据也将开始 解决在考虑之前必须回答的问题 这些药物中可能适用于人类的癌症问题。 生化研究的重点是确定 这些药物与DNA聚合酶和核糖核酸还原酶的作用 主要的行动地点。对每个其他势能的影响 酶靶标--二氢叶酸还原酶、胸苷合成酶和dNMP 将使用纯化的酶制剂以及 野生型和耐药突变体中的通透性细胞。基于 作用机制：抗肿瘤细胞基础的耐人寻味问题 选择性，特别是在非黑色素瘤细胞中，将使用 肿瘤细胞和来源的骨髓细胞的短期培养 L1210荷瘤小鼠。希望这将使我们能够定量地检查 在抗肿瘤选择性的基础上，可能显示出显著的 肿瘤细胞和正常细胞之间的代谢差异可能是 根本意义。我们打算，这种多方面的方法将 继续产生重要的生物数据，这些数据可以立即 应用于改良剂的合成，同时获得了 必要的数据来确定这些药物中的哪些似乎是合理的 以继续在人类身上进行终极临床试验。

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.