Breast Cancer Resistance to Cyclophosphamide and Other Oxazaphosphorines.
Abstract
Cyclophospharnide is the most widely used drug in the treatment of breast cancer. Unfortunately, emergence of drug- resistant tumor cell populations limits its usefulness. Class-I and class-3 aldehyde dehydrogenases (ALDH-1 and ALDH- 3, respectively) have been shown to catalyze the detoxification of cyclophosphamide and other oxazaphosphorines. Predictably, then, relatively elevated levels of ALDH-I and ALDH-3 have been shown to account for resistance to these agents in several cultured breast and other tumor cell models. It follows that cellular resistance to these agents on the part of clinical breast cancers could be due to overexpression of ALDH-1 and/or ALDH-3. Our finding that elevated levels of ALDH-1 and ALDH-3 are present in some primary and metastatic breast tumor tissues supports this notion. Although nearly identical, tumor cell ALDH-3 appears to be different from normal cell ALDH-3. A tumor-specific ALDH-3 would have diagnostic potential. Tumor cell ALDH-3 was found to be more sensitive to inhibition by each of five chlorpropamide analogs than was normal cell ALDH-3 suggesting that selective sensitization of tumor cells to cyclophosphamide and other oxazaphosphorines may be possible when tumor cell insensitivity to these drugs is due to high levels of ALDH-3. Xenobiotics that are abundantly present in the diet/environment, e.g., methylcholanthrene and catechol, rapidly, coordinately and reversibly induced ALDH-3 and other drug metabolizing enzymes in cultured breast land 9ther cancer cell models, thus, rapidly effecting reversible multienzyme-mediated multidrug resistance/collateral sensitivity to cyclophosphamide and certain other anticancer drugs.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1995
- Accession Number
- ADA307635
Entities
People
- Norman E. Sladek
Organizations
- University of Minnesota