Depletion of O6-alkylguanine-DNA alkyltransferase correlates with potentiation of temozolomide and CCNU toxicity in human tumour cells.
Depletion of O6-alkylguanine-DNA alkyltransferase correlates with potentiation of temozolomide and CCNU toxicity in human tumour cells.
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DOI：
10.1038/bjc.1993.241
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发表时间：
1993-06
影响因子：
8.8
通讯作者：
Margison, G P
中科院分区：
文献类型：
--
作者：
Baer, J C;Freeman, A A;Newlands, E S;Watson, A J;Rafferty, J A;Margison, G P
替莫唑胺（8-氨基甲酰基-3-甲基咪唑[5，1-d]-1，2，3，5-四嗪-4-（3 H）-酮）在I期试验中显示出对某些脑癌（神经胶质瘤）和皮肤癌（黑色素瘤、蕈样肉芽肿）的良好活性。替莫唑胺和洛莫司汀（CCNU）在7种人肿瘤细胞系中显示出平行毒性，这通常与DNA修复蛋白O 6-烷基鸟嘌呤-DNA烷基转移酶（ATase，EC 2.1.1.63）的表达水平相关（相关系数分别为0.87和0.92）。预处理细胞与AT酶抑制剂，O 6-苄基鸟嘌呤（BG），增强细胞毒性与两种药物的相似程度，但没有敏感的细胞系（ZR-75-1）表达非常低水平的这种蛋白质。当BG预处理与重复剂量的替莫唑胺组合时，在表达高水平AT酶的MAWI细胞中观察到显著增强（300倍），但在表达低水平AT酶的细胞系（U373）中未观察到。[14 C]-标记的替莫唑胺摄取在敏感和耐药品系中相似。人ATase-cDNA转染着色性干皮病（XP）成纤维细胞比XP对照细胞更耐替莫唑胺和相关的氯乙基化剂米托唑胺，虽然BG完全抑制这些细胞中的ATase活性，电阻仍然大于对照细胞。
Temozolomide (8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4-(3H)-one) has shown promising activity in Phase I trials against some brain (glioma) and skin (melanoma, mycosis fungoides) cancers. Temozolomide and lomustine (CCNU) showed parallel toxicity in seven human tumour cell lines and this generally correlated (correlation coefficients 0.87 and 0.92 respectively) with the level of expression of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase, EC 2.1.1.63). Pretreating cells with the ATase inhibitor, O6-benzylguanine (BG), potentiated cytotoxicity to a similar degree with both drugs, but did not sensitise a cell line (ZR-75-1) expressing very low levels of this protein. When BG pretreatment was combined with repeat doses of temozolomide a dramatic potentiation (300 fold) was seen in MAWI cells, which express high levels of ATase, but not in a cell line (U373) expressing lower levels of ATase. [14C]-labelled temozolomide uptake was similar in sensitive and resistant lines. Human ATase-cDNA transfected xeroderma pigmentosum (XP) fibroblasts were more resistant than XP control cells to temozolomide and the related chloroethylating agent mitozolomide and although BG completely suppressed ATase activity in these cells, resistance was still greater than in control cells.