Hypoxanthine concentrations in normal subjects and patients with solid tumors and leukemia

Abstract

Mean plasma hypoxanthine (Hyp) concentrations determined by high-pressure liquid chromatography were 0.56 microM (range, 0.2 to 1.9 microM) in 16 normal subjects, 0.68 microM (range, 0.1 to 1.1 microM) in 10 untreated acute leukemic subjects, and 0.89 microM (range, 0.3 to 2.6 microM) in 14 solid tumor patients. Despite large differences in Hyp concentration between patients, every 4-hr sampling, indicated that diurnal variation in individual patients was small (maximum, 2.3-fold). While the mean plasma and malignant effusion Hyp concentrations did not differ significantly, bone marrow plasma Hyp concentration averaged 4.0-fold greater than that of simultaneously drawn venous plasma. Allopurinol 300 mg p.o. caused a mean 1.5-fold increase in plasma Hyp within 3 hr. In 17 patients with acute leukemia, treatment with allopurinol at 300 mg daily plus initiation of chemotherapy caused a mean 7-fold increase in plasma Hyp to 4.6 microM (range, 1 to 12 microM). The ability of Hyp to modulate the toxicity of antimetabolites affecting purine synthesis (6- diazao -5- oxonorleucine , 6-methylmercaptopurine riboside, 6-mercaptopurine, and 6-thioguanine) was determined in vitro using human B-lymphoblast (WI-L2) and promyelocytic leukemia (HL-60) cell lines. Hyp permitted growth of both cell lines in the presence of clinically achievable concentrations of all 4 drugs, but the initial culture concentrations of Hyp required were above those found in patients. Since Hyp was consumed rapidly during the culture period, the average Hyp concentrations required for the protection of cells were actually much lower. We conclude that, in patients with acute leukemia receiving allopurinol during chemotherapy, plasma Hyp concentrations are significantly elevated; the potential for antagonism of antimetabolite activity is uncertain.