Purine analogues were used in this study to dissect specific steps in the mechanism of action of nerve growth factor (NGF). Protein kinase N (PKN) is an NGF-activated serine protein kinase that is active in the presence of Mn++. The activity of PKN was inhibited in vitro by purine analogues, the most effective of which was 6-thioguanine (apparent Ki = 6 microM). Several different criteria indic...

Several 9-alkyl, 6-thiopurines have been reported to have more favorable therapeutic indexes than do the parent drugs, 6-mercaptopurine (MP) and 6-thioguanine (TG). Some of these compounds were reported to be active against cells in culture resistant to 6-thiopurines, and it has been assumed that their mechanisms of action may differ from those of TG and MP. 9-(n-Butyl)-6-thioguanine was essent...

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One ...

Drug repositioning is the application of the existing drugs to new uses and has the potential to reduce the time and cost required for the typical drug discovery process. In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two successive oxidations in melanin biosynthesis: the conversions of tyrosine to dih...

1. Reinshagen M, Schutz E, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, et al. 6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active Crohn disease: results from a randomized, controlled, open trial. Clin Chem 2007;53:1306–14. 2. Shipkova M, Armstrong VW, Wieland E, Oellerich M. Differences in nucleotide hydr...

AIM We evaluated the effect of coadministration of sulphasalazine, mesalamine, and balsalazide on the pharmacokinetics and pharmacodynamics of azathioprine and 6-mercaptopurine. METHODS Thirty four patients with Crohn's disease receiving azathioprine or 6-mercaptopurine were enrolled in an eight week non-randomised parallel group drug interaction study and treated with mesalamine 4 g/day, sul...

We have measured the forward mutation rate at the hypoxanthine Phosphoribosyltransferase (HPRT) gene of the human promyelocytic leukemia cell line III,-6(1 and have determined the molecular spectrum of spontaneous HPRT mutations in 45 independent 6-thioguanine-resistant HL-60 sublines. Four fluctuation tests using a total of 132 replicate 111,-60 cultures revealed a mean forward mutation rate o...

Thioguanine-resistant T lymphoblast populations were selectively amplified using T cell growth factor in the cultures of peripheral blood T cells from four Lesch-Nyhan heterozygotes. Although Lesch-Nyhan T lymphoblasts were all thioguanine-resistant, none of the cultures from 13 control subjects yielded the growth of such defective cell populations. These data provide direct evidence for the ex...

Extensive efforts by the Burroughs-Wellcome group, the Sloan-Kettering group, and others have led to a considerable knowledge of purine antagonists that inhibit the growth of bacteria, experimental neoplasms, and human leukemias (18). Although 6-mercaptopurine (6-MP) is the most widely employed purine antagonist from the clinical standpoint, "related compounds, thioguanine, 6-chloropurine, 6-me...

The traditional approach to dosing anticancer drugs is to administer a standard starting dose, which is normalized to body surface area, and then to adjust or individualize subsequent doses based on the severity of ensuing drug toxicity. Dosing according to body surface area is based on the assumption that the volume of distribution and drug elimination mechanisms are proportional to the body s...