Therapeutic synergism elicited by the combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride: synergistic cytocidal activity against L1210 cells in vitro.

In order to clarify the mechanism of therapeutic synergism elicited by a combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), the cytocidal activity towards L1210 leukemic cells in vitro of these two drugs, alone and in combination, was examined by the soft agar cloning assay and the regrowth assay methods. More than 10-fold greater cell-killing activity than the expected additive survival (the product of fractional survival obtained for each drug alone) was observed on treatment with the combination of these drugs in both assay methods. More-over, dose- and treatment schedule-dependent antitumor activity of this combination treatment against L1210 leukemia in vivo was clearly reflected in the cytocidal activity towards L1210 cells in vitro. These findings suggest that the therapeutic synergism elicited by the combination of ACNU and 6-thioguanine results from synergistic cytocidal activity towards tumor cells.