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Leukocyte Purine Phosphoribosyltransferases in Human Leukemias Sensitive and Resistant to 6-Thiopurines¹

Laboratory of Medical Genetics, Medical Service, San Francisco General Hospital, San Francisco, California 94110

The levels of leukocyte adenine phosphoribosyltransferase and of hypoxanthine-guanine phosphoribosyltransferase (H-GPRT) were compared in normal control subjects, patients with acute leukemia in remission, and patients with acute leukemia in exacerbation. Significant (p < 0.025) elevations of both the adenine phosphoribsosyltransferase and H-GPRT activities occurred in individuals with leukemia in replase, compared with those in remission. Altered ratios of the specific enzymatic activities of adenine phosphoribosyltransferase to H-GPRT were noted in two of eight 6-thiopurine-resistant patients. Leukemic cells from one patient with chronic myelogenous leukemia in blast crisis exhibited a marked decrease in H-GPRT activity. The H-GPRT from the second patient showed an altered affinity for purine bases and, most markedly, for 5'-phosphoribosyl-1-pyrophosphate when 6-mercaptopurine was used as substrate. The finding of these two patients with mutant H-GPRT and a reevaluation of results obtained in 6-mercaptopurine-resistant patients in a previously published series led us to the conclusion that, in human acute leukemia, resistance to 6-thiopurines may be accounted for by deficient or altered H-GPRT in a significant number of cases.

¹ This work was supported by Special Fellowship Grant 1-F3-CA-51, 545-01 from the National Cancer Institute and, in part, by USPHS Grant AM 13672.

² Special fellow of the Leukemia Society of America. To whom reprint requests should be addressed, at Yale New Haven Medical Center, Department of Medicine, Oncology Section, New Haven, Conn. 06510.

Received 11/ 2/72. Accepted 2/27/73.