MODULATION OF NITROSOUREA RESISTANCE IN HUMAN COLON CANCER BY O6-METHYLGUANINE
MODULATION OF NITROSOUREA RESISTANCE IN HUMAN COLON CANCER BY O6-METHYLGUANINE
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DOI：
10.1016/0006-2952(92)90618-s
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发表时间：
1992-03-03
影响因子：
5.8
通讯作者：
WILLSON, JKV
中科院分区：
文献类型：
--
作者：
GERSON, SL;BERGER, NA;WILLSON, JKV
人类结肠癌对包括亚硝基脲在内的多种烷化剂具有抗性。为了具体评估亚硝基脲抗性，我们研究了已知修复亚硝基脲诱导的细胞毒性DNA损伤的O 6-烷基鸟嘌呤-DNA烷基转移酶（烷基转移酶）的作用。在25例结肠癌活检和14个结肠癌细胞系中，烷基转移酶活性在类似的宽范围内变化，但活性与分化状态、Dukes分类或体外生长特性无关。7种结肠癌细胞系对1，3-二-（2-氯乙基）-l-亚硝基脲（BCNU）的耐药性与烷基转移酶活性高度相关（R2 = 0.929，P < 0.001），表明烷基转移酶是结肠癌细胞对亚硝基脲耐药性的重要组成部分。在BCNU耐药的高烷基转移酶VACO 6细胞系中，O 6-甲基鸟嘌呤对烷基转移酶的失活导致BCNU IC 50成比例降低，与回归线预测的结果一致。酶失活也与DNA交联形成的显著增加有关。由于烷基转移酶与结肠癌中的BCNU抗性相关，并且抗性可以通过使蛋白质失活来逆转，因此烷基转移酶可能在人类结肠癌细胞中的亚硝基脲抗性中具有重要作用。这些数据提供了在结肠癌中使用烷基转移酶的生化调节剂以增加对亚硝基脲的治疗反应的临床试验的基本原理。
Human colon cancer is resistant to a variety of alkylating agents including the nitrosoureas. To specifically evaluate nitrosourea resistance, we studied the role of O6-alkylguanine-DNA alkyltransferase (alkyltransferase) which is known to repair nitrosourea-induced cytotoxic DNA damage. Alkyltransferase activity varied over a similar wide range in 25 colon cancer biopsies and 14 colon cancer cell lines but the activity was not correlated with differentiation status, Dukes' classification or in vitro growth characteristics. 1,3-Bis-(2-chloroethyl)-l-nitrosourea (BCNU) resistance and alkyltransferase activity were highly correlated (R2 = 0.929, P < 0.001) in 7 different colon cancer cell lines, suggesting that the alkyltransferase is an important component of nitrosourea resistance in colon cancer cells. In the BCNU-resistant, high alkyltransferase VACO 6 cell line, inactivation of the alkyltransferase by O6-methylguanine caused a proportional decrease in the BCNU IC50, consistent with that predicted by the regression line. Enzyme inactivation was also associated with a marked increase in DNA cross-link formation. Because alkyltransferase correlates with BCNU resistance in colon cancer, and resistance can be reversed by inactivating the protein, the alkyltransferase may have an important role in nitrosourea resistance in human colon cancer cells. These data provide the rationale for clinical trials in colon cancer with biochemical modulators of the alkyltransferase to increase the therapeutic response to nitrosoureas.