Mechanisms of resistance to 6-thiopurines in human leukemia.

The activities of enzymes involved in the formation and catabolism of 6-thiopurine nucleotide were assayed in leukocytes of leukemic patients considered either suscepti ble or resistant to the 6-thiopurines. Altered ratios of the activities of hypoxanthine-guanine phosphoribosyltransferase (H-GPRT) and adenine phosphoribosyltransferase were noted in leukocytes from 3 of 11 resistant acute nonlymphocytic leukemic (ANLL) patients, whereas nor mal ratios were found in all 7 resistant acute lymphocytic leukemic patients assayed. Leukocytes from one of the re sistant ANLL patients had a marked decrease in H-GPRT activity, while the remainder were relatively deficient, as defined by an adenine phosphoribosyltransferase/H-GPRT (A/H) ratio greater than the average ratio from leuko cytes of untreated patients plus 3 standard deviation units. Particulate-bound alkaline phosphatase was significantly elevated in leukocytes from 2 of 11 resistant ANLL and 6 of 7 resistant acute lymphocytic leukemia patients. Little correlation between acid phosphatase levels of leukemic leukocytes and clinical status was noted. Increased alkaline phosphatase activity tended to occur in resistant patients with normal adenine phosphoribosyltransferase/H-GPRT ratios. The findings suggested that either a decrease in H-GPRT or an increase in alkaline phosphatase activities was responsible, at least in part, for insensitivity to 6thiopurines in 5 of 11 ANLL and 6 of 7 acute lymphocytic leukemia patients.