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Enhancement of the Frequency of Methotrexate Resistance by -Radiation in Chinese Hamster Ovary and Mouse 3T6 Cells¹

Department of Biological Sciences, Stanford University, Stanford, California 94305

We have studied the effects of -radiation on the frequency of methotrexate resistance and dihydrofolate reductase gene amplification. -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 -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 -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.

¹ This work was supported by Research Grant CA-16318 from the National Cancer Institute.

Received 11/15/88. Revised 3/14/89. Accepted 4/12/89.

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