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, ISSN: 0022-3565, Vol: 301, Issue: 1, Page: 77-86
2002
- 31Citations
- 23Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations31
- Citation Indexes31
- 31
- CrossRef26
- Captures23
- Readers23
- 23
Article Description
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. Furthermore, after in vivo treatment of mice with the prodrugs, no reduction was observed in circulating white blood cell counts, whereas white blood cell counts of mice treated with equimolar or 60% lower doses of 6-TG were reduced by 50 to 60%. Collectively, the results show that AVTG and AVTP are novel potential chemotherapeutic agents that may target tumors with up-regulated levels of GSH, and may exhibit less systemic toxicity than the parent thiopurines.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S002235652435579X; http://dx.doi.org/10.1124/jpet.301.1.77; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0036129205&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/11907160; https://linkinghub.elsevier.com/retrieve/pii/S002235652435579X; https://dx.doi.org/10.1124/jpet.301.1.77; https://jpet.aspetjournals.org/content/301/1/77
Elsevier BV
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