烷化剂马法兰耐药细胞系L_（1210）／Mel的建立及其耐药机制的研究

ALKYLATING AGENT MELPHALANRESlSTANT CELLLINES (L_(1210)/Mel): ESTABLISHMENT,CHARACTERISTICS AND ITS MECHANlSMS OFRESISTANCE

应用逐步增加剂量的方法在体外建立两株耐不同剂量马法兰（Ｍｅｌ）的小鼠白血病细胞系，命名为Ｌ＿（１２１０）／Ｍｅｌ＿１及Ｌ＿（１２１０）／Ｍｅｌ＿２，它们分别对Ｍｅｌ耐药３．６倍及９．９倍，后者对氮芥及噻哌有明显交叉耐药，而对卡氮芥及阿霉素仍敏感。我们发现随着Ｍｅｌ耐药水平增加，其谷胱甘肽－Ｓ－转移酶（ＧＳＴ）总量及ＧＳＴα基因表达水平明显增加，而ＧＳＴπ轻度升高，多药耐药基因ＭＤＲ－１及ＧＳＴμ基因表达水平无明显升高，表明ＧＳＴα基因与马法兰耐药密切相关。此外，还检测了马法兰诱导的ＤＮＡ交联率，结果发现耐药株在４小时后ＤＮＡ交联宰低于敏感株，在２４小时ＤＮＡ交联得到完全恢复。这表明耐药株中ＤＮＡ损伤减少，而ＤＮＡ修复功能大大增强。

wo leukemic cell lines (L_(1210)/Mel , and L_(1210)/Mel_2) ,which were stably resistant to Mel for 3. 6 and 9. 9 foldrespectively were established. L_(1210)/Mel_2 was also crossresistant to nitrogen mustards and thiotepa ,but it failedto show any increased resistance to carmustine and dox-orubicin. This enhanced drug resistance was assoriatedwith increase in the expression level ofαandπclass ofGST gene and total GST, but not with increase in theexpression level ofμclass of GST gene and MDR-1gene. The DNA interstrand crosslinks of L,,,.IMel, decreased after 4 hours of melphalan induction and completely repaired at 24 hours. It suggested that the DNAdamage of the L_(1210)/Mel_2 decreased and the repair capa-bility enhanced when treated with Mel.