PLEIOTROPIC DRUG-RESISTANCE AND SURVIVAL ADVANTAGE IN LEUKEMIC-CELLS WITH DIMINISHED APOPTOTIC RESPONSE
PLEIOTROPIC DRUG-RESISTANCE AND SURVIVAL ADVANTAGE IN LEUKEMIC-CELLS WITH DIMINISHED APOPTOTIC RESPONSE
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DOI：
10.1002/ijc.2910590214
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发表时间：
1994-10-15
影响因子：
6.4
通讯作者：
SUGARBAKER, EV
中科院分区：
文献类型：
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作者：
FRANKFURT, OS;SECKINGER, D;SUGARBAKER, EV
通过连续暴露于MOLT-4细胞以阿霉素产生的细胞系R9对多种不相关的药物具有交叉耐药性。以下数据表明，减少的凋亡反应是获得性多效性药物抗性的机制：（i）凋亡是表达交叉抗性的药剂的细胞死亡的常见机制;（ii）在R9细胞中，药物、培养基消耗和血清剥夺对凋亡的诱导减少;（iii）凋亡细胞中的DNA降解在抗性系中较低，可能反映了抗性细胞中凋亡途径的改变;（iv）药物对敏感细胞和耐药细胞的细胞分裂和DNA合成的抑制作用相似。这些数据表明类似水平的初始损伤，如基于修饰的凋亡反应的抗性的典型。bcl-2蛋白在敏感细胞和耐药细胞中的表达无明显差异。因此，获得多效性电阻和减少凋亡反应的R9细胞诱导的bcl-2的非依赖性机制。表面T细胞抗原CD 4下调在乳腺癌相关耐药中的作用仍有待探讨。获得性多效性耐药和在不利生长条件下生存能力增加之间的关联表明，药物诱导的细胞凋亡反应减弱的细胞选择可能刺激肿瘤进展。烷化剂诱导类似的细胞毒性和仅略低于MOLT-4细胞相比，在R9细胞的凋亡。我们的数据表明，一些药物可以克服获得性多效性耐药的基础上修改的凋亡途径。(C)1994 Wiley-Liss，Inc.
Cell line R9 generated by continuous exposure to MOLT-4 cells to adriamycin was cross-resistant to a variety of unrelated drugs. The following data indicate that diminished apoptotic response was the mechanism of acquired pleiotropic drug resistance: (i) apoptosis was a common mechanism of cell death for agents expressing cross-resistance; (ii) induction of apoptosis by drugs, medium depletion and serum deprivation was decreased in R9 cells; (iii) DNA degradation in apoptotic cells was lower in resistant lines, probably reflecting a modification of apoptotic pathway in resistant cells; (iv) inhibition of cell division and DNA synthesis by drugs was similar in sensitive and resistant cells. These data indicated a similar level of initial damage, as typical for resistance based on modified apoptotic response. There was no difference in bcl-2 protein level between sensitive and resistant cells. Thus acquired pleiotropic resistance and diminished apoptotic response in R9 cells were induced by a bcl-2-independent mechanism. Surface T-cell antigen CD4 down-regulation in apoptosis-related drug resistance remains to be explored. The association between acquired pleiotropic drug resistance and increased survival capacity in unfavorable growth conditions indicated that drug-induced selection of cells with diminished apoptotic response may stimulate neoplastic progression. Alkylating agents induced similar cytotoxicity and only slightly lower apoptosis in R9 cells in comparison with MOLT-4 cells. Our data show that some drugs may overcome acquired pleiotropic drug resistance based on the modified apoptotic pathway. (C) 1994 Wiley-Liss, Inc.