Breast Cancer Resistance to Cyclophosphamide and Other Oxazaphosphorines

Cyclophosphamide is perhaps the most widely used drug in the treatment of breast cancer. Unfortunately, its use is rarely curative because cyclophosphamide-resistant tumor cell populations rapidly emerge. Our investigations sought to identify at least one mechanism by which cyclophosphamide resistance is effected, thereby providing the rationale for strategies that would reverse or even prevent it. At a minimum, the expectation was that our studies would identify a prognostic determinant that could be used to identify patients for whom cyclophosphamide therapy wound be futile, thus sparing them that therapy and the accompanying untoward effects. Two suspects were identified in preclinical models, viz., the enzymes ALDH3A1 and ALDH1A1. Each was found to catalyze the inactivation of cyclophosphamide. Therefore, the more there was of either of these enzymes in cancer cells, the better able they were to defend themselves against this drug. Amounts of these enzymes in clinical breast cancer samples were found to vary over a 300-fold range. Moreover, ALDH3A1 levels could be increased more than 200-fold in cultured breast cancer cells by exposing them to any of several chemicals that are commonly present in various foods and beverages, e.g., broccoli and coffee. Three agents, each potentially useful in overcoming ALDH3A1-mediated cyclophosphamide-resistance, were identified. Retrospective studies established that ALDH1A1 levels in clinical breast cancers were of sufficient magnitude to affect the clinical outcome of cyclophosphamide-based chemotherapy, whereas those of ALDH3A1 were not.