Bodell W J, Gerosa M, Aida T, Berger M S, Rosenblum M L
Cancer Res. 1985 Aug;45(8):3460-4.
The 9L-2, 9L-7, and 9L-8 cell lines, derived from the 9L in vivo rat brain tumor, were treated with nitrosoureas that can alkylate and cross-link DNA and carbamoylate intracellular molecules to various extents. Compared to 9L cells, 9L-2 cells were very resistant to the cytotoxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, and to 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-deoxyglucopyranose. The sensitivity of 9L-7 and 9L-8 cell lines to these drugs was intermediate between 9L and 9L-2. Treatment of 9L, 9L-2, 9L-7, and 9L-8 cell lines with 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea produced approximately the same level of cell kill. Compared to 9L cells, 9L-2 cells are 10-fold more resistant to the cytotoxic effects, 34-fold more resistant to the induction of sister chromatid exchanges, and have 40% fewer DNA interstrand cross-links caused by treatment with 3-(4-amino-2-methyl-5-pyrimidinyl)methyl-1-(2-chloroethyl)-1-nitrosourea . In contrast, treatment of 9L and 9L-2 cells with 1-ethylnitrosourea produced approximately the same level of cell kill and induction of sister chromatid exchanges. Our results suggest that the resistance of 9L-2, 9L-7, and 9L-8 cells is related to DNA cross-linking and not to alkylation or carbamoylation. We studied the effects of other agents that form DNA cross-links with structures different from those formed by treatment with chloroethylnitrosoureas (CENUs) in 9L and 9L-2 cells. In contrast to results obtained with CENUs, 9L-2 cells were 2-fold more sensitive to the cytotoxic effects, 2-fold more sensitive to the induction of sister chromatid exchanges, and had 3-fold more cross-links formed than 9L cells treated with nitrogen mustard. However, the amount of cell kill, number of sister chromatid exchanges induced, and the DNA cross-linking were the same for 9L and 9L-2 cells treated with cis-diamminedichlorplatinum(II). Our results indicate that cellular resistance to CENUs is highly specific and that the mechanism of resistance does not allow cross-resistance with other DNA cross-linking agents. These and other results suggest that when DNA repair processes mediate cellular resistance to CENUs, other cross-linking agents will not be cross-resistant unless they form alkylation products that are affected by repair processes that mediate resistance to CENUs.
源自9L大鼠体内脑肿瘤的9L - 2、9L - 7和9L - 8细胞系，用可使DNA烷基化和交联以及使细胞内分子不同程度氨甲酰化的亚硝基脲处理。与9L细胞相比，9L - 2细胞对1,3 - 双（2 - 氯乙基）- 1 - 亚硝基脲和2 - [3 - （2 - 氯乙基）- 3 - 亚硝基脲基] - D - 脱氧葡萄糖的细胞毒性作用具有很强的抗性。9L - 7和9L - 8细胞系对这些药物的敏感性介于9L和9L - 2之间。用1,3 - 双（反式 - 4 - 羟基环己基）- 1 - 亚硝基脲处理9L、9L - 2、9L - 7和9L - 8细胞系产生了大致相同程度的细胞杀伤。与9L细胞相比，9L - 2细胞对细胞毒性作用的抗性高10倍，对姐妹染色单体交换诱导的抗性高34倍，并且用3 - （4 - 氨基 - 2 - 甲基 - 5 - 嘧啶基）甲基 - 1 - （2 - 氯乙基）- 1 - 亚硝基脲处理后产生的DNA链间交联少40%。相比之下，用1 - 乙基亚硝基脲处理9L和9L - 2细胞产生了大致相同程度的细胞杀伤和姐妹染色单体交换诱导。我们的结果表明，9L - 2、9L - 7和9L - 8细胞的抗性与DNA交联有关，而与烷基化或氨甲酰化无关。我们研究了其他与9L和9L - 2细胞中氯乙基亚硝基脲（CENUs）形成不同结构DNA交联的试剂的作用。与CENUs的结果相反，9L - 2细胞对细胞毒性作用的敏感性高2倍，对姐妹染色单体交换诱导的敏感性高2倍，并且与用氮芥处理的9L细胞相比形成的交联多3倍。然而，用顺 - 二氨二氯铂（II）处理的9L和9L - 2细胞的细胞杀伤量、诱导的姐妹染色单体交换数以及DNA交联是相同的。我们的结果表明，细胞对CENUs的抗性具有高度特异性，并且抗性机制不允许与其他DNA交联剂产生交叉抗性。这些以及其他结果表明，当DNA修复过程介导细胞对CENUs的抗性时，除非其他交联剂形成受介导对CENUs抗性的修复过程影响的烷基化产物，否则它们不会产生交叉抗性。
