Cellular levels of class 1 and class 3 aldehyde dehydrogenases and certain other drug-metabolizing enzymes in human breast malignancies.

Abstract

Molecular determinants of cellular sensitivity to cyclophosphamide, long the mainstay of chemotherapeutic regimens used to treat metastatic breast cancer, include class 1 and class 3 aldehyde dehydrogenases (ALDH-1 and ALDH-3, respectively), which catalyze the detoxification of this agent. Thus, interindividual variation in the activity of either of these enzymes in breast cancers could contribute to the wide variation in clinical responses that are obtained when such regimens are used to treat these malignancies. Consistent with this notion, ALDH-1 levels in primary and metastatic breast malignancies were found to range from 1-276 and 8-160 mIU/g tissue, respectively, and those of ALDH-3 range from 1-242 and 6-97 mIU/g tissue, respectively. ALDH-1 and ALDH-3 levels in normal breast tissue predicted the levels of these enzymes in primary and metastatic breast malignancies present in the same individuals. Confirming and extending the observations of others, levels of glutathione, a molecular determinant of cellular sensitivity to various DNA cross-linking agents including cyclophosphamide, and of DT-diaphorase, glutathione S-transferases, and cytochrome P450 1A1, each of which is known to catalyze the detoxification/toxification of one or more anticancer agents (although not of cyclophosphamide), also varied widely in primary and metastatic breast malignancies. Given the wide range of ALDH-1, ALDH-3, and glutathione levels that were observed in malignant breast tissues, measurement of their levels in normal breast tissue and/or primary breast malignancies prior to the initiation of chemotherapy is likely to be of value in predicting the therapeutic potential, or lack thereof, of cyclophosphamide in the treatment of metastatic breast cancer, thus providing a rational basis for the design of individualized therapeutic regimens when treating this disease.