TUMOR-CELL HETEROGENEITY - IMPACT ON MECHANISMS OF THERAPEUTIC DRUG-RESISTANCE

Purpose: The aim of these studies was to determine whether chemotherap y-resistant tumor cell sublines derived from a single starting cell po pulation with identical treatment protocols, have the same mechanism o f resistance. Methods and Materials: Twelve cyclophosphamide-resistant sublines were derived from KHT-iv murine sarcoma cells by repeated ex posures to 2, 4, or 8 mu g/ml doses of 4-hydroperoxycyclophosphamide ( 4-OOHCP), To investigate possible mechanisms of resistance, glutathion e (GSH) levels, glutathione S-transferase (GST) activity, and aldehyde dehydrogenase (ALDH) activity were determined, In addition, studies w ith the GSH depletor buthionine sulfoximine (BSO) and the ALDH inhibit or diethylamino-benzaldehyde (DEAB) were undertaken. Results: Resistan t factors to 4-OOHCP, assessed at 10% clonogenic cell survival, ranged from 1.5-7.0 for the various cell lines, Crossresistance to melphalan and adriamycin also were commonly observed, Increased GSH levels, GST activity and ALDH activity were detected in the sublines but not all exhibited the same pattern of biochemical alterations. The response to GSH and ALDH inhibitors also varied among the sublines; the resistanc e being reversible in some cell lines but not others. Conclusion: The present results indicate that when resistant sublines are derived simu ltaneously from the same starting cell population, the observed mechan isms of resistance may not be the same in each of the variants, These findings support the hypothesis that preexisting cellular heterogeneit y may affect mechanisms of acquired resistance. (C) 1997 Elsevier Scie nce Inc.