Deveopment of resistance to combinations of six antimetabolites in mice with L1210 leukemia.

The development of resistance to combinations of 6-mercaptopurine, 6-thioguanine, 6-methylmercaptopurine riboside, methotrexate, 5-fluorouracil, and cytosine arabinoside was studied in L1210 leukemia through 60 transfer generations. The treatment schedules were either simultaneous or offset. In simultaneous administration, one sixth of the LD10 of each of the six drugs was administered within a few minutes, daily for 6 days. In offset administration, the drugs were given either in the above-listed order or in reversed order, with one drug given each day. In the simultaneous combination treatment protocol 31 transfer generations were necessary to reach partial resistance, but in the two offset combination schedules only five and three generations were needed. The relative rate of development of resistance to the individual drugs was slower in the three combination schedules than in single-drug schedules. Resistance to 6-mercaptopurine and 6-thioguanine was completed after four generations on the offset combination schedules, but only after 28 generations on the simultaneous schedule.