Drug sensitivity of heat-resistant mouse B16 melanoma variants.
Induction of transient thermotolerance by heat or other cytotoxic stressors has been reported to confer a moderate degree of drug resistance to tumor cells in vitro. In this study, a genetically stable, heat-resistant mouse B16 melanoma variant (W-H75) was tested for its sensitivity to various cytotoxic and antiproliferative agents. The heat-resistant W-H75 cells displayed a moderate two- to threefold resistance to doxorubicin, VP-16, VM-26, colchicine, cis-dichlorodiammineplatinum(II), HgCl2, and CdCl2. Marginal resistance to 4'(9-acridinylamino)methanesulfon-m-anisidide vinblastine, 1,3-bis(2-chloroethyl)-1-nitro-sourea, and NaAsO2 was observed, while no difference in sensitivity to the anticancer drugs, actinomycin D and camptothecin, was observed. Although W-H75 cells were generally more resistant than the parental cells to most of the agents that were tested, they were collaterally sensitive to the antimetabolites methotrexate and 6-mercaptopurine. Resistance of the W-H75 cells to epipodophyllotoxins and anthracyclines was not due to differences in steady-state drug accumulation. For the epipodophyllotoxin VP-16, resistance may be related to a relative decrease in the number of drug-induced DNA strand breaks in W-H75 cells. However, no difference in DNA strand breakage was observed between W-H75 and parental cells which were treated with doxorubicin, suggesting that resistance to this drug occurred by a different mechanism. The possible involvement of glutathione and glutathione S-transferase in resistance was also investigated. The glutathione content in W-H75 cells was 35% higher than that in the parental line. However, glutathione S-transferase activity appeared to be identical in both cell lines. Two other heat-resistant B16 melanoma variants, B-H103 and R-H92, were also tested for sensitivity to doxorubicin and VP-16. In contrast to the W-H75 cells, these two heat-resistant variants were hypersensitive to doxorubicin. The B-H103 cells were also hypersensitive to VP-16. This study suggests that selection for cellular resistance to heat may result in cells that have an altered sensitivity to drugs.
Kroll
D J
DJ
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville 32610.
Borgert
C J
CJ
Wiedmann
T W
TW
Rowe
T C
TC
D000064:Acclimatization / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004273:DNA, Neoplasm / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000187:drug effects; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004361:Drug Tolerance / Q000502:physiology; D005047:Etoposide / Q000493:pharmacokinetics / Q000494:pharmacology; D014644:Genetic Variation / Q000502:physiology*; D006358:Hot Temperature; D066298:In Vitro Techniques; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D005047:Etoposide; D004317:Doxorubicin; D003630:Daunorubicin