DNA TOPOISOMERASE I-TARGETED THERAPY OF COLONIC CANCER

一类新型化疗药物，具有前所未有的 对人结肠癌移植瘤的有效性已在 我们的初步研究。该提案提出了一种合成喜树碱的方案 类似物，在临床前筛查中进行测试，最终用于 结肠癌的化疗。因此，该项目代表着一种专注的 致力于药物开发分子、细胞和肿瘤生物学。理性的人 该计划的基础是由参与者进行的试点研究 实验室在过去的几年里。该计划的主要目标 项目包括： 1.加快9-氨基-20(RS)，10，11-的临床前评估工作 亚甲二氧基-20(RS)喜树碱及其水溶性同系物。 2.全合成20(S)异构体的制备与开发 喜树碱类似物，以及具有新性质的类似物，如增加 TOPO-I-DNA可裂解络合物或E(内酯)环的稳定性 药物分子，以及提高了整体疗效。 3.利用TOPO-I定向检测系统筛选新的类似物 治疗人类结肠癌。从头学习和后天学习的机制研究 对喜树碱类似物耐药。 4.对选定的高效亲脂剂和水进行并排测试- 可溶的同系物，使用一组成熟的和特征良好的 人结肠癌细胞系在组织培养和AS中的增殖 裸鼠异种移植。药物的药代动力学和毒性研究。 5.将一到两个靶向类似物带入临床试验。

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.