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Reversal of Resistance to Methotrexate by Hyperthermia in Chinese Hamster Ovary Cells¹

Departments of Internal Medicine [T. S. H., C. S.], and Radiology [A. E. C., E. W. G.], University of Arizona College of Medicine, Tucson, Arizona 85724

Our Chinese hamster ovary cells are extremely resistant to methotrexate (MTX) (100% survival after 500 µg/ml for 13 hr). However, exposure to 43° (but not 41° or 42°) for 1 hr sensitizes the cells to MTX so that a 50% cell kill in excess of that due to hyperthermia occurs. Treatment of cells at 43° increases net MTX uptake by about 30% at 30 min but causes a substantial reduction after 1 hr. This negative effect is greater in cells continually heated at 43° than in those exposed for only 1 hr. Treatment at 43° for 1 hr also markedly increases efflux of MTX out of cells over the first 2 hr. Dihydrofolate reductase activity was found to decrease to about 50% of control values by 4 to 5 hr after exposure to 43°. The biological half-life of dihydrofolate reductase in Chinese hamster ovary cells was determined to be about 4.5 hr, indicating that hyperthermia-induced cessation of protein synthesis may explain both the decrease in dihydrofolate reductase activity and the sensitization to MTX observed with heat exposure. In scheduling experiments, lethality due to exposure to 43° for 1 hr in conjunction with MTX was maximum when 1-hr drug exposure began just at the end of heat treatment.

¹ Supported in part by Grants CA 26220 and CA 17343 and in part by Research Advisory Group, Veterans Administration, Tucson, Ariz. 85723.

Received 10/23/80. Accepted 6/29/81.