9-Aminocamptothecin and beyond. Preclinical and clinical studies.
9-Aminocamptothecin and beyond. Preclinical and clinical studies.
复制标题
9-氨基喜树碱及其他。
DOI：
10.1111/j.1749-6632.1996.tb26393.x
复制
发表时间：
1996
影响因子：
5.2
通讯作者：
Hochster,H
中科院分区：
文献类型：
--
作者：
Potmesil,M;Arbuck,SG;Takimoto,CH;Liebes,L;Hochster,H
9-氨基喜树碱（9-aminocamptothecin，9-AC，NSC 603071）是最早合成并应用于临床的喜树碱类化合物。这种药物最近被引入临床试验。这种后期临床应用主要是由于需要开发具有低水溶性的药物的药理学制剂。生物化学、与靶DNA拓扑异构酶I（topo I）的相互作用以及9-AC和其他喜树碱发挥细胞毒性的机制已得到广泛研究（在参考文献的几章中进行了综述）。第3和第4段）。在top 0 I定向筛选和组织培养中对其结构-活性关系的研究之后，测试了细胞9-AC针对在免疫缺陷小鼠中作为异种移植物生长的固有抗性人类癌症。在生物学研究中，将9-AC、母体20（S）-喜树碱（CPT）和其它相关类似物溶解在强有机溶剂如DMSO中，或配制成在吐温80中的悬浮液：盐水或在基于脂质的介质中。在大多数异种移植物实验中，在4-6周的时间内以2次/周的时间表皮下（sc）或肌内（im）注射9-AC混悬液。在所有治疗的小鼠中，这种治疗在SC植入的肿瘤中诱导完全反应（CR）。'-I0
Although 9-aminocamptothecin (9-AC, NSC 603071) was the first among the camptothecins synthesized for clinical application,'.'the drug was introduced to clinical testing recently. This late clinical application was mainly due to the need to develop pharmacological formulation of the drug with low water solubility. The biochemistry, interaction with the target DNA topoisomerase I (topo I), and the mechanism of cytotoxicity exerted by 9-AC and other camptothecins, have been studied extensively (reviewed in several chapters of refs. 3 and 4). Following studies of its structure-activity relationships in top0 I-directed screens and in tissue-culture cell 9-AC was tested against inherently resistant human cancers growing as xenografts in immunodeficient mice. The spectrum of xenografts included three lines of colon carcinoma, malignant melanoma, infiltrating ductal carcinoma of the breast, two types of non-small cell lung carcinoma, and an epithelial line of ovarian cancer.In biological studies, 9-AC, the parental 20 (S)-camptothecin (CPT) and other related analogs were dissolved in strong organic solvents such as DMSO, or formulated as a suspension in Tween 80: saline or in lipid-based media. In most xenograft experiments, 9-AC suspension was injected subcutaneously (sc) or intramuscularly (im) on a 2 x/week schedule over a period of 4-6 weeks. Such treatment induced complete responses (CR) in SC implanted tumors in all treated mice.'-I0