Tumor cell heterogeneity: impact on mechanisms of therapeutic drug resistance.
OBJECTIVE
The aim of these studies was to determine whether chemotherapy-resistant tumor cell sublines derived from a single starting cell population with identical treatment protocols, have the same mechanism of resistance.


METHODS
Twelve cyclophosphamide-resistant sublines were derived from KHT-iv murine sarcoma cells by repeated exposures to 2, 4, or 8 microg/ml doses of 4-hydroperoxycyclophosphamide (4-OOHCP). To investigate possible mechanisms of resistance, glutathione (GSH) levels, glutathione S-transferase (GST) activity, and aldehyde dehydrogenase (ALDH) activity were determined. In addition, studies with the GSH depletor buthionine sulfoximine (BSO) and the ALDH inhibitor diethylamino-benzaldehyde (DEAB) were undertaken.


RESULTS
Resistant 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 resistance being reversible in some cell lines but not others.


CONCLUSIONS
The present results indicate that when resistant sublines are derived simultaneously from the same starting cell population, the observed mechanisms of resistance may not be the same in each of the variants. These findings support the hypothesis that preexisting cellular heterogeneity may affect mechanisms of acquired resistance.
Richardson
M E
ME
Department of Radiation Oncology, Shands Cancer Center, University of Florida, Gainesville 32610-0385, USA.
Siemann
D W
DW
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism* / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008558:Melphalan / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012513:Sarcoma, Experimental / Q000201:enzymology* / Q000473:pathology; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D009363:Neoplasm Proteins; D003520:Cyclophosphamide; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D005978:Glutathione; D008558:Melphalan; C011272:perfosfamide