PMID: 11907160Mar 22, 2002Paper

Novel glutathione-dependent thiopurine prodrugs: evidence for enhanced cytotoxicity in tumor cells and for decreased bone marrow toxicity in mice

The Journal of Pharmacology and Experimental Therapeutics
Sjofn GunnarsdottirAdnan A Elfarra

Abstract

Elevated glutathione (GSH) levels have been detected in many tumors compared with the healthy, surrounding tissue. Often, this GSH up-regulation is associated with drug resistance. The prodrugs 6-(2-acetylvinylthio)guanine (AVTG) and 6-(2-acetylvinylthio)purine (AVTP) contain a novel butenone moiety that allows the prodrugs to react selectively with sulfhydryl nucleophiles to release the chemotherapeutic drug 6-thioguanine (6-TG) or 6-mercaptopurine (6-MP), respectively. The cellular uptake and metabolism of trans-AVTG in two human renal carcinoma cell lines that were used as models were rapid and associated with depletion of intracellular GSH. Formation of 6-TG from trans-AVTG correlated positively with intracellular GSH concentrations, and was significantly reduced by diethyl maleate pretreatment. Intracellular concentrations of 6-TG after incubations with trans-AVTG were significantly higher than the 6-TG concentrations obtained after incubations with equimolar concentrations of 6-TG; thus, the prodrug delivered more 6-TG to the cell than did 6-TG itself. Cytotoxicity studies demonstrated that AVTG and AVTP had similar IC(50) values that were comparable with those of 6-TG, but were significantly lower than those of 6-MP. Fur...Continue Reading

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Citations

Sep 1, 2005·Toxicology and Applied Pharmacology·Christopher L Sprague, Adnan A Elfarra
May 14, 2003·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Wei WangWenrui Jin
Apr 17, 2007·Biochemical Pharmacology·Birgitta I EklundBengt Mannervik
Aug 27, 2014·Frontiers in Pharmacology·Emma E Ramsay, Pierre J Dilda
Sep 8, 2012·Molecular Pharmaceutics·André J van der VliesJeffrey A Hubbell
Aug 14, 2018·Expert Opinion on Drug Discovery·Xin-Yu Zhang, Adnan A Elfarra
Dec 5, 2013·Pharmaceutics·Paolo Ruzza, Andrea Calderan
Feb 12, 2018·ACS Biomaterials Science & Engineering·Jorge A GutiérrezClaudia C Ortiz

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