Aldehyde dehydrogenase-mediated cellular relative insensitivity to the oxazaphosphorines

As judged by findings in preclinical models, determinants of cellular sensi tivity to cyclophosphamide and other oxazaphosphorines include two cytosoli c aldehyde dehydrogenases, viz., ALDH1A1 and ALDH3A1. Each catalyzes the de toxification of the oxazaphosphorines; thus, cellular sensitivity to these agents decreases as cellular levels of ALDH1A1 and/or ALDH3A1 increase. Of particular clinical relevance may be that stable sublines, relatively insen sitive to the oxazaphosphorines due to elevated ALDH1A1 or ALDH3A1 levels, emerged when cultured human tumor cells were exposed only once to a high co ncentration of one of these agents for 30 to 60 minutes. Whether difference s in cellular levels of either enzyme accounts for the clinically-encounter ed uneven therapeutic effectiveness of the oxazaphosphorines remains to be determined. However, it has already been established that measurable levels of these enzymes are found in some, but not all, tumor types, and that in those tumor types where measurable levels are present, e.g., infiltrating d uctal carcinomas of the breast, they vary widely from patient to patient. P otentially useful clinical strategies that might be pursued if it turns out that ALDH1A1 and/or ALDH3A1 are, indeed, clinically operative determinants of cellular sensitivity to the oxazaphosphorines include 1) individualizin g cancer chemotherapeutic regimens based, at least in part, on the levels o f these enzymes in the malignancy of interest, and 2) sensitizing tumor cel ls that express relatively large amounts of ALDH1A1 and/or ALDH3A1 to the o xazaphosphorines by preventing the synthesis of these enzymes, e.g., with a ntisense RNA, or by introducing an agent that directly inhibits the catalyt ic action of the operative enzyme. Further, the fact that ALDH1A1 and ALDH3 A1 are determinants of cellular sensitivity to the oxazaphosphorines provid es the rationale for the investigation of two additional strategies with cl inical potential, viz., decreasing the sensitivity of vulnerable and essent ial normal cells, e.g., pluripotent hematopoietic cells, to the oxazaphosph orines by selectively transferring into them the genetic information that e ncodes 1) ALDH1A1 or ALDH3A1, or 2) a signaling factor, the presence of whi ch would directly or indirectly, stably upregulate the expression of these enzymes.