DNA TOPOISOMERASE I-TARGETED THERAPY OF COLONIC CANCER

一类新的化疗药物，具有前所未有的 已经确定了对人结肠癌异种移植物的有效性， 我们的试点研究。 该提案提出了合成喜树碱的计划 类似物，在临床前筛选中对其进行测试，以最终用于 结肠癌的化疗 因此，该项目代表了一个重点 致力于药物开发分子、细胞和肿瘤生物学。 合理 该计划的基础上进行的试点研究，参与 实验室在过去几年。 的主要目标 项目包括： 1.加速9-氨基-20（RS）、10，11- 亚甲二氧基-20（RS）喜树碱及其水溶性同系物。 2.全合成20（s）异构体的制备和开发 喜树碱类似物和具有新性质的类似物，如增加的 topo-I-DNA可切割复合物或E（内酯）环的稳定性 药物分子，以及改善的整体有效性。 3.设计了使用拓扑异构酶-I定向测定系统筛选新类似物的方法， for human人类colonic结肠cancer癌症. 原发性和获得性肿瘤发生机制的研究 对喜树碱类似物的抗性。 4.对选定的高效亲脂性和水溶性材料进行并行测试- 可溶性同系物，使用一组已确定并充分表征的 人结肠癌细胞系，在组织培养中增殖， 在裸鼠中的异种移植物。 药物药代动力学和毒性研究。 5.将一两种靶向类似物用于临床试验。

A class of novel chemotherapeutic agents, with an unprecedented effectiveness against human colon cancer xenografts, has been identified in our pilot study. The proposal presents a plan to synthesize camptothecin analogs, to test them in preclinical screens for eventual use in chemotherapy of colonic cancer. As such, the project represents a focused effort in drug development molecular, cell and tumor biology. The rational of the program is based on pilot studies conducted by participating laboratories over the past several years. The principal objectives of the project include: 1. Accelerated effort in preclinical evaluation of 9-amino-20(RS),10,11- methylenedioxy-20(RS) camptothecins and their water-soluble congeners. 2. Preparation and development of totally synthetic 20(s) isomers of camptothecin analogs, and analogs with novel properties, such as increased stability of the topo-I-DNA cleavable complex or the E (lactone) ring of the drug molecule, as well as improved overall effectiveness. 3. Screening of new analogs using topo-I-directed assay systems, designed for human colonic cancer. Studies of the mechanism of de-novo and acquired resistance to camptothecin analogs. 4. Side-by-side testing of selected highly effective lipophilic and water- soluble congeners, using a panel of established and well characterized lines of human colon carcinoma, propagated in tissue culture and as xenografts in nude mice. Studies of drug pharmacokinetics and toxicity. 5. Bringing one or two target analogs to clinical trials.