Sreerama L, Rekha G K, Sladek N E
Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455.
Biochem Pharmacol. 1995 Mar 1;49(5):669-75. doi: 10.1016/0006-2952(94)00503-e.
High-level cytosolic class-3 aldehyde dehydrogenase (ALDH-3)-mediated oxazaphosphorine-specific resistance (> 35-fold as judged by the concentrations of mafosfamide required to effect a 90% cell-kill) was induced in cultured human breast adenocarcinoma MCF-7/0 cells by growing them in the presence of 30 microM catechol for 5 days. Resistance was transient in that cellular sensitivity to mafosfamide was fully restored after only a few days when the inducing agent was removed from the culture medium. The operative enzyme was identified as a type-1 ALDH-3. Cellular levels of glutathione S-transferase and DT-diaphorase activities, but not of cytochrome P450 IA1 activity, were also elevated. Other phenolic antioxidants, e.g. hydroquinone and 2,6-di-tert-butyl-4-hydroxytoluene, also induced ALDH-3 activity when MCF-7/0 cells were cultured in their presence. Thus, the increased expression of a type-1 ALDH-3 and the other enzymes induced by these agents was most probably the result of transcriptional activation of the relevant genes via antioxidant responsive elements present in their 5'-flanking regions. Cellular levels of ALDH-3 activity were also increased when a number of other human tumor cell lines, e.g. breast adenocarcinoma MDA-MB-231, breast carcinoma T-47D and colon carcinoma HCT 116b, were cultured in the presence of catechol. These findings should be viewed as greatly expanding the number of recognized environmental and dietary agents that can potentially negatively influence the sensitivity of tumor cells to cyclophosphamide and other oxazaphosphorines.
在30微摩尔儿茶酚存在的情况下，将培养的人乳腺腺癌MCF-7/0细胞培养5天，可诱导高水平的胞质3类醛脱氢酶（ALDH-3）介导的恶唑磷特异性抗性（根据实现90%细胞杀伤所需的马磷酰胺浓度判断，抗性超过35倍）。抗性是短暂的，因为当从培养基中去除诱导剂后，仅几天细胞对马磷酰胺的敏感性就完全恢复了。起作用的酶被鉴定为1型ALDH-3。谷胱甘肽S-转移酶和DT-黄递酶的细胞水平也升高了，但细胞色素P450 IA1活性没有升高。当MCF-7/0细胞在其他酚类抗氧化剂（如对苯二酚和2,6-二叔丁基-4-甲基苯酚）存在的情况下培养时，也会诱导ALDH-3活性。因此，这些试剂诱导的1型ALDH-3和其他酶表达的增加很可能是通过其5'侧翼区域存在的抗氧化反应元件对相关基因进行转录激活的结果。当一些其他人类肿瘤细胞系（如乳腺腺癌MDA-MB-231、乳腺癌T-47D和结肠癌HCT 116b）在儿茶酚存在的情况下培养时，ALDH-3活性的细胞水平也会增加。这些发现应被视为极大地扩展了可潜在负面影响肿瘤细胞对环磷酰胺和其他恶唑磷敏感性的公认环境和膳食试剂的数量。
