CELLULAR-LEVELS OF CLASS-1 AND CLASS-3 ALDEHYDE DEHYDROGENASES AND CERTAIN OTHER DRUG-METABOLIZING-ENZYMES IN HUMAN BREAST MALIGNANCIES

Molecular determinants of cellular sensitivity to cyclophosphamide, lo ng the mainstay of chemotherapeutic regimens used to treat metastatic breast cancer, include class 1 and class 3 aldehyde dehydrogenases (AL DH-1 and ALDH-3, respectively), which catalyze the detoxification of t his agent. Thus, interindividual variation in the activity of either o f these enzymes in breast cancers could contribute to the wide variati on in clinical responses that are obtained when such regimens are used to treat these malignancies. Consistent with this notion, ALDH-1 leve ls in primary and metastatic breast malignancies were found to range f rom 1-276 and 8-160 mIU/g tissue, respectively, and those of ALDH-3 ra nge 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 i n primary and metastatic breast malignancies present in the same indiv iduals. Confirming and extending the observations of others, levels of glutathione, a molecular determinant of cellular sensitivity to vario us DNA cross-linking agents including cyclophosphamide, and of DT-diap horase, glutathione S-transferases, and cytochrome P450 1A1, each of w hich is known to catalyze the detoxification/toxification of one or mo re anticancer agents (although not of cyclophosphamide), also varied w idely in primary and metastatic breast malignancies. Given the wide ra nge of ALDH-1, ALDH-3, and glutathione levels that were observed in ma lignant breast tissues, measurement of their levels in normal breast t issue and/or primary breast malignancies prior to the initiation of ch emotherapy is likely to be of value in predicting the therapeutic pote ntial, or lack thereof, of cyclophosphamide in the treatment of metast atic breast cancer, thus providing a rational basis for the design of individualized therapeutic regimens when treating this disease.