REVERSAL OF RESISTANCE TO METHOTREXATE BY HYPERTHERMIA IN CHINESE-HAMSTER OVARY CELLS

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (10) , 3840-3843
Abstract
Chinese hamster ovary cells are extremely resistant to [the antineoplastic drug] methotrexate (MTX) (100% survival after 500 .mu.g/ml for 13 h). Exposure to 43.degree. C (but not 41.degree. or 42.degree. C) for 1 h sensitizes the cells to MTX so that a 50% cell kill in excess of that due to hyperthermia occurs. Treatment of cells at 43.degree. C increases net MTX uptake by .apprx. 30% at 30 min but causes a substantial reduction after 1 h. This negative effect is greater in cells continually heated at 43.degree. C than in those exposed for only 1 h. Treatment at 43.degree. C for 1 h also markedly increases efflux of MTX out of cells over the first 2 h. Dihydrofolate reductase activity decreased to .apprx. 50% of control values by 4-5 h after exposure to 43.degree. C. The biological half-life of dihydrofolate reductase in Chinese hamster ovary cells was .apprx. 4.5 h, indicating that hyperthermia-induced cessation of protein synthesis may explain the decrease in dihydrofolate reductase activity and the sensitization to MTX observed with heat exposure. In scheduling experiments, lethality due to exposure to 43.degree. C for 1 h in conjunction with MTX was maximum when 1 h drug exposure began just at the end of heat treatment.