SOME OBSERVATIONS ON THE COMBINED EFFECTS OF X-RAYS AND METHOTREXATE ON HUMAN TUMOR CELLS IN VITRO WITH POSSIBLE RELEVANCE TO THEIR MOST USEFUL COMBINATION IN RADIOTHERAPY

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Abstract
The lethal effects of methotrexate upon human tumor cells in vitro depend not only upon the concentration of the drug around those cells, but also upon the length of time for which the drug and the cells remain in contact. Short-term exposure to even very high concentrations of methotrexate may leave a large proportion of tumor cells intact, while longer exposures to lower drug concentrations will leave few cells capable of repeated divisions. Exposure of human tumor cells to concentrations of methotrexate which are nonlethal nonetheless sensitizes those cells to subsequent x-irradiation. Tumor cells which survive exposure to higher, cell-killing concentrations of methotrexate are protected less by anoxia than untreated cells when they are irradiated immediately afterwards. When irradiated immediately after exposure to the drug, methotrexate-treated cells show no recovery from sublethal x-ray damage; if irradiated 24 hours or more after their removal from methotrexate, those tumor cells which have survived are capable of recovery between fractionated x-ray doses and show no reduction in anoxic protection. These results in a relatively simple single-cell system are examined in the context of treatment schemes used in the several published clinical studies of radiotherapy combined with methotrexate chemotherapy. A plan is proposed for the optimum combination of these two agents.

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