At-Assa S, Porcher J M, Kretz-Remy C, Velarde G, Arrigo A P, Lambre C
Laboratoire de Biochimie et Toxicologie in vitro, Institut National de l'Environnement Industriel et des Risques (INERIS), F-60550 Verneuil-en-Halatte, France.
Toxicol In Vitro. 1999 Aug-Oct;13(4-5):651-5. doi: 10.1016/s0887-2333(99)00032-6.
HeLa cells containing the chloramphenicol acetyl transferase (CAT) gene under the control of the hsp70 promoter have been exposed in vitro to various anticancer drugs. Cisplatin induced CAT production with a dose-effect relationship at a non-cytotoxic dose, whereas no induction was detected with carboplatin. Etoposid induced a significant response at a cytotoxic concentration. The limited positive response with doxorubicin, daunomycin and mitoxantrone was not statistically significant. These chemicals are known to produce reactive oxygen species and induce apoptosis. No induction of the hsp70 promoter could be detected with the other cytostatic compounds that have been tested such as base analogues (5-fluorouracil, cytosine arabinoside 3'-MP), inhibitors of DNA synthesis (amethopterin, aminopterin), antimitotics (vinblastine, colchicine), and alkylating (streptozotocine, carboplatin, melphalan) or intercalating agents (bleomycin). In addition, the role of the transcription inhibitory activity of doxorubicin in this model is evidenced and the consequent question of the suitability of the reporter gene system is discussed. Our results suggest that specific genotoxic compounds are not able to induce the hsp70 promoter, and are in agreement with the concept that stimulation of HSP70 synthesis occurs through a biochemical process involving proteotoxicity.
含有在热休克蛋白70（hsp70）启动子控制下的氯霉素乙酰转移酶（CAT）基因的HeLa细胞已在体外暴露于各种抗癌药物。顺铂在非细胞毒性剂量下以剂量效应关系诱导CAT产生，而卡铂未检测到诱导作用。依托泊苷在细胞毒性浓度下诱导了显著反应。阿霉素、柔红霉素和米托蒽醌的有限阳性反应无统计学意义。已知这些化学物质会产生活性氧并诱导细胞凋亡。对于已测试的其他细胞生长抑制剂，如碱基类似物（5-氟尿嘧啶、阿糖胞苷、3'-MP）、DNA合成抑制剂（氨甲蝶呤、氨基蝶呤）、抗有丝分裂剂（长春碱、秋水仙碱）以及烷基化剂（链脲佐菌素、卡铂、美法仑）或嵌入剂（博来霉素），均未检测到hsp70启动子的诱导作用。此外，还证实了阿霉素在该模型中转录抑制活性的作用，并讨论了报告基因系统适用性的相关问题。我们的结果表明，特定的基因毒性化合物无法诱导hsp70启动子，这与通过涉及蛋白毒性的生化过程刺激HSP70合成的概念相符。
