ENHANCED INVITRO SELECTIVE TOXICITY OF CHEMOTHERAPEUTIC-AGENTS FOR HUMAN CANCER-CELLS BASED ON A METABOLIC DEFECT
ENHANCED INVITRO SELECTIVE TOXICITY OF CHEMOTHERAPEUTIC-AGENTS FOR HUMAN CANCER-CELLS BASED ON A METABOLIC DEFECT
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DOI：
10.1093/jnci/76.4.629
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发表时间：
1986-04-01
影响因子：
10.3
通讯作者：
HOFFMAN, RM
中科院分区：
文献类型：
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作者：
STERN, PH;HOFFMAN, RM
利用人类癌细胞系中普遍存在的代谢缺陷来选择性杀死这些细胞，而不杀死共培养的正常人类成纤维细胞。蛋氨酸依赖性是一种仅在体外癌细胞或永生化细胞系中发现的代谢缺陷，它阻止细胞在蛋氨酸被其直接前体同型半胱氨酸取代的培养基中生长，这种情况允许所有测试的正常细胞株生长。在上述条件下，蛋氨酸依赖性细胞在 S-G2 晚期（即晚期 S 期和 G2 期）被可逆性阻断，这种阻断被用于针对这些细胞的选择性化疗。在用等量的癌细胞和人二倍体成纤维细胞起始的培养物中，用同型半胱氨酸和阿霉素替代培养基中的甲硫氨酸，然后用长春新碱补充甲硫氨酸，对于选择性消除甲硫氨酸依赖性人类肉瘤和3种甲硫氨酸依赖性人类癌完全有效。上述方案对于部分不依赖甲硫氨酸的肉瘤回复体几乎完全有效。所使用的化疗程序对与肿瘤细胞一起生长的正常细胞并不致命，并且当完全在含蛋氨酸的培养基中进行时是无效的。最佳程序是在不含甲硫氨酸、含有同型半胱氨酸的培养基中加入10-10M多柔比星10天，然后进行2次。 10-7 M 长春新碱在含蛋氨酸、不含同型半胱氨酸的培养基中培养 1 天，然后依次加入不含药物的含蛋氨酸、不含同型半胱氨酸的培养基。这些结果证明了基于正常细胞和肿瘤细胞之间代谢差异的化疗治疗实体瘤的潜力。
A metabolic defect that is prevalent in human cancer cell lines was exploited to selectively kill these cells without killing cocultural normal human fibroblasts. Methionine dependence, a metabolic defect seen only in cancer cells or immortalized cell lines in vitro, precludes the cells from growing in media in which methionine is replaced by its immediate precursor, homocysteine, a condition that allows the growth of all normal cell strains tested. The methionine-dependent cells become reversibly blocked in late S-G2 (i.e., late-S and G2 phases) under the above condition, a block that was exploited for selective chemotherapy against these cells. In cultures that were initiated with equal amounts of cancer cells and human diploid fibroblasts, substitution of homocysteine and doxorubicin for methionine in the culture medium followed by methionine repletion with vincristine was totally effective at selectively eliminating a methionine-dependent human sarcoma and 3 methionine-dependent human carcinomas. The above protocol wasa nearly totally effective against a partially methionine-independent revertant of the sarcoma. The chemotherapeutic procedure used was not lethal to normal cells growing alongside the tumor cells and was ineffective when conducted totally in methionine-containing medium. The optimal procedure was 10-10 M doxorubicin in methionine-free, homocysteine-containing medium for 10 days followed by 2 .times. 10-7 M vincristine in methionine-containing, homocysteine-free medium for 1 day, in turn followed by drug-free methionine-containing, homocysteine-free medium. These results demonstrate the potential for treatment of solid tumors with chemotherapy based on metabolic differences between normal and tumor cells.