Paradoxical behavior of 6-mercaptopurine as a cytotoxic agent: decreasing cell kill with increasing drug dose

9L rat brain tumor cells were continuously exposed to "low" (2.9 microM) and "high" (18 and 35 microM) doses of 6-mercaptopurine (6-MP); cell kill was measured with a colony forming efficiency assay. The low dose of 6-MP killed more cells than the high doses, as measured by surviving fraction, when they were treated for greater than 48 hours. Even though the total number of cells increased during the 72-hour treatment period, the number of clonogenic cells decreased most when cells were treated with the low dose of 6-MP. Data obtained with flow cytometry suggest that for the high dose there was a drug-induced block of cells in the G1 phase that prevented them from progression into S phase where they would be killed.