PHENOLIC ANTIOXIDANT-INDUCED OVEREXPRESSION OF CLASS-3 ALDEHYDE DEHYDROGENASE AND OXAZAPHOSPHORINE-SPECIFIC RESISTANCE

High-level cytosolic class-3 aldehyde dehydrogenase (ALDH-3)-mediated oxazaphosphorine-specific resistance (> 35-fold as judged by the conce ntrations of mafosfamide required to effect a 90% cell-kill) was induc ed in cultured human breast adenocarcinoma MCF-7/0 cells by growing th em in the presence of 30 mu M catechol for 5 days. Resistance was tran sient in that cellular sensitivity to mafosfamide was fully restored a fter only a few days when the inducing agent was removed from the cult ure medium. The operative enzyme was identified as a type-1 ALDH-3. Ce llular levels of glutathione S-transferase and DT-diaphorase activitie s, but not of cytochrome P450 IA1 activity, were also elevated. Other phenolic antioxidants, e.g. hydroquinone and 2,6-di-tert-butyl-4-hydro xytoluene, also induced ALDH-3 activity when MCF-7/0 cells were cultur ed 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 antioxi dant responsive elements present in their 5'-flanking regions. Cellula r 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 pr esence of catechol. These findings should be viewed as greatly expandi ng the number of recognized environmental and dietary agents that can potentially negatively influence the sensitivity of tumor cells to cyc lophosphamide and other oxazaphosphorines.