Enhancement of the frequency of methotrexate resistance by gamma-radiation in Chinese hamster ovary and mouse 3T6 cells.
We have studied the effects of gamma-radiation on the frequency of methotrexate resistance and dihydrofolate reductase gene amplification. gamma-Irradiation of Chinese hamster ovary cells resulted in enhancement of the frequency of methotrexate resistant colonies (maximum enhancement: 2000-fold after 1000 rads). The enhancement of methotrexate resistance was dependent on the dose of gamma-radiation and increased with time after irradiation; a maximum enhancement was observed when methotrexate was added 18 h after irradiation. Methotrexate resistant clones of Chinese hamster ovary cells showed no increase in dihydrofolate reductase gene copy number but were found to be defective in methotrexate transport. However, when these experiments were extended to 3T6 murine cells, 54% of nonirradiated and 44% of gamma-radiation induced methotrexate resistant clones showed an increase in dihydrofolate reductase gene copy number. These results suggest that the cells that survive irradiation have a very high probability of becoming methotrexate resistant and may explain why some malignant tumors (e.g., head and neck cancer) either do not respond or respond poorly to chemotherapy if the patient had prior radiotherapy.
Sharma
R C
RC
Department of Biological Sciences, Stanford University, California 94305.
Schimke
R T
RT
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D002999:Clone Cells; D006224:Cricetinae; D003412:Cricetulus; D004307:Dose-Response Relationship, Radiation; D004351:Drug Resistance / Q000528:radiation effects*; D005260:Female; D005720:Gamma Rays; D005796:Genes / Q000187:drug effects / Q000528:radiation effects; D007700:Kinetics; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D010053:Ovary; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate