Schedule-dependent synergism and antagonism between methotrexate and 6-mercaptopurine in a human acute lymphoblastic...

We studied the combined cytotoxic effects of methotrexate and 6-mercaptopurine (6-MP) on a human acute lymphoblastic cell line (MOLT-3) in vitro according to various schedules. The combined effects were analysed with improved isobologram using the concept of additivity. Simultaneous and continuous exposure (72 h) to these two agents had subadditive to protective effects (antagonism). Partial simultaneous exposure to methotrexate (5 h) and 6-MP (72 h) showed additive to protective effects. Sequential exposure to methotrexate (5 h) followed by 6-MP (72 h) had an additive effect at 0 h and a supra-additive effect (synergism) at 3 h and 19 h intervals. Therefore, it would seem to be better to avoid the simultaneous administration of methotrexate and 6-MP when these two drugs are used in combination. Sequential administration of methotrexate first, followed by 6-MP at short intervals, is recommended.