Comparison of thymidine and folinic acid protection from methotrexate toxicity in human lymphoid cell lines

Hypoxanthine, thymidine, and folinic acid protection from methotrexate cytotoxicity were compared in human lymphoid cell lines variably sensitive to thymidine-induced growth suppression. Hypoxanthine protection differed among the cell lines, and the dose-response relationship for protection occurred within the physiologic bone marrow hypoxanthine concentration range. The slopes of the thymidine protection curves were virtually superimposable in a B cell line versus a T cell line, but threefold to fourfold higher thymidine concentrations were required to maximally protect the B versus the T cell line. Thymidine (plus hypoxanthine) protection was superior to that of folinic acid in both the B and the T cell lines when protection was delayed. As the interval between methotrexate and folinic acid exposure was progressively delayed, there was a linear decline in the degree of maximum protection in both cell lines. However, as thymidine exposure was progressively delayed, maximal protection was maintained, except at 12 hours in the B cell line. The influence of methotrexate on thymidine-induced growth suppression was studied. Methotrexate enhanced thymidine-induced growth suppression in sensitive cells as manifested by a significant shift of the dose-response curve. Deoxycytidine protection from thymidine toxicity was superior in the presence of methotrexate. The results of these studies indicate that thymidine protection and folinic acid protection against methotrexate toxicity produce different effects, which in part are dependent on the cell type. The complexity of these interactions points out the need for further studies.