Reversal of 6-mercaptopurine and 6-methylmercaptopurine ribonucleoside cytotoxicity by amidoimidazole carboxamide ribonucleoside in Molt F4 human malignant T-lymphoblasts

Purine metabolism and the microaerophily of Helicobacter pylori

“…The mechanisms of 6-thiopurine, 6-thioguanine, and 6-methylmercaptopurine riboside toxicity in several mammalian cells grown under conditions that depend on the de novo pathway of purine synthesis is a pseudofeedback inhibition of the first committed step of the pathway (glutamine phosphoribosylpyrophosphate amidotransferase, EC 2.4.2.14) by nucleotides synthesized from these precursors (McCollister et al 1964;Henderson and Mercer 1966;Hill and Bennett 1969;Bennett and Adamson 1970;Cohen and Sadee 1983;Sokoloski and Sartorelli 1987). In some cell lines grown under conditions in which purines are synthesized entirely de novo, blockade of the pathway by 6-thiopurine, 2-AMP, or 6-methylmercaptopurine riboside can be reversed noncompetitively by preformed purines or intermediates of purine synthesis (Nelson et al 1975;Bökkerink et al 1993;Stet et al 1993Stet et al , 1995. In cell cultures in which the de novo pathway is blocked and growth is totally dependent on a supplement of purines added to the media, the lethal effects of 6-thiopurine, 6-thioguanine, and 6-methylmercaptopurine riboside appear to be due to the formation of thioguanine nucleotides and their incorporation into DNA and RNA (Tidd and Paterson 1974;Grindley et al 1976).…”

Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine

“…AICAR, which is an intermediate of purine de novo synthesis distal to the MeSPuRMP inhibition site [22], providing further evidence for the cytotoxic MeSPuRMP in sd that the cytotoxic effect of MeSPuRMP in these cells is the first step in the purine biosynthetic pathway.…”

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

“…Previously, methylated 6MP metabolites were considered largely insignificant for 6MP pharmacodynamics. However, some methylated metabolites, not least methylthioinosine monophosphates (MeMP), are strong inhibitors of purine de novo synthesis 77. As the purine salvage pathway is low in lymphoblasts that primarily depend on purine de novo synthesis,78 the reduced levels of endogenous nucleotides and the resulting enhanced DNA-TG incorporation in the presence of MeMP is likely to play a clinical role 74,79.…”