DNA TOPOISOMERASE-I TARGETED CHEMOTHERAPY OF HUMAN-COLON CANCER IN XENOGRAFTS
DNA TOPOISOMERASE-I TARGETED CHEMOTHERAPY OF HUMAN-COLON CANCER IN XENOGRAFTS
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DOI：
10.1126/science.2555920
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发表时间：
1989-11-24
期刊：
影响因子：
56.9
通讯作者：
POTMESIL, M
中科院分区：
文献类型：
--
作者：
GIOVANELLA, BC;STEHLIN, JS;POTMESIL, M
需要进行药物研发以改进局部晚期或转移性结肠癌患者的化疗，否则这些患者预后不良。DNA拓扑异构酶I是一种对解决DNA复制过程中出现的拓扑问题以及其他细胞功能都很重要的核酶，已被确定为植物生物碱20(S)-喜树碱的主要靶点。与正常结肠黏膜相比，在人类结肠腺癌的晚期以及免疫缺陷小鼠携带的结肠癌异种移植物中发现这种酶的浓度显著升高。通过对纯化酶的测试和组织培养筛选，选择了几种喜树碱的合成类似物，并在异种移植物模型中进行了评估。与所测试的其他抗癌药物不同，20(RS)-9 - 氨基 - 喜树碱（9 - AC）诱导了无病缓解。总体药物毒性较低，允许重复疗程的治疗。
Drug development is needed to improve chemotherapy of patients with locally advanced or metastatic colon carcinoma, who otherwise have an unfavorable prognosis. DNA topoisomerase I, a nuclear enzyme important for solving topological problems arising during DNA replication and for other cellular functions, has been identified as a principal target of a plant alkaloid 20 (S)-camptothecin. Significantly increased concentrations of this enzyme, compared to that in normal colonic mucosa, were found in advanced stages of human colon adenocarcinoma and in xenografts of colon cancer carried by immunodeficient mice. Several synthetic analogs of camptothecin, selected by tests with the purified enzyme and tissue-culture screens, were evaluated in the xenograft model. Unlike other anticancer drugs tested, 20 (RS)-9-amino-camptothecin (9-AC) induced disease-free remissions. The overall drug toxicity was low and allowed for repeated courses of treatment.