Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine

Stet, E. H.; Abreu, Ronney A. De; Bökkerink, J.P.M.; Lambooy, Lambert H.J.; Vogels-Mentink, Trude M.; Keizer-Garritsen, Jenneke J.; Trijbels, Frans J.M.

doi:10.1016/0006-2952(94)00387-2

Cited by 25 publications

(10 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In support of the latter possibility, our findings demonstrating that the addition of adenosine, guanosine, hypoxanthine, and inosine can block the activation of Nurr1 by 6-MP are consistent with previous studies showing that the cytotoxic effects of 6-MP can be reversed or inhibited by replenishing the pool of nucleotides through the addition of adenosine or guanosine (42). The activation of Nurr1 in CV-1 cells and other cell lines tested is observed at 10 M 6-MP and increases with increasing concentrations of 6-MP.…”

Section: -Mercaptopurine Controls Nurr1 Transcription Activitysupporting

confidence: 80%

“…The antiproliferative activity of 6-MP has been shown to result partly from a decrease in the production of adenosine and guanosine synthesis (42). To determine if depletion of these nucleotides had any effect on Nurr1, 6-MP was added in the presence of adenine, adenosine, guanine, guanosine, hypoxanthine, or inosine.…”

Section: -Mercaptopurine Activation Of Nurr1 Can Be Blocked By Replementioning

confidence: 99%

See 1 more Smart Citation

Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1

Ordentlich

Yan

Zhou

et al. 2003

Journal of Biological Chemistry

103

View full text Add to dashboard Cite

The purine anti-metabolite 6-mercaptopurine is one of the most widely used drugs for the treatment of acute childhood leukemia and chronic myelocytic leukemia. Developed in the 1950s, the drug is also being used as a treatment for inflammatory diseases such as Crohn's disease. The antiproliferative mechanism of action of this drug and other purine anti-metabolites has been demonstrated to be through inhibition of de novo purine synthesis and incorporation into nucleic acids. Despite the extensive clinical use and study of 6-mercaptopurine and other purine analogues, the cellular effects of these compounds remain relatively unknown. More recently, purine anti-metabolites have been shown to function as protein kinase inhibitors and to regulate gene expression. In an attempt to find small molecule regulators of the orphan nuclear receptor Nurr1, interestingly, we identified 6-mercaptopurine as a specific activator of this receptor. A detailed analysis of 6-mercaptopurine regulation of Nurr1 demonstrates that 6-mercaptopurine regulates Nurr1 through a region in the amino terminus. This activity can be inhibited by components of the purine biosynthesis pathway. These findings indicate that Nurr1 may play a role in mediating some of the antiproliferative effects of 6-mercaptopurine and potentially implicate Nurr1 as a molecular target for treatment of leukemias.The Nobel prize-winning work of Elion et al.(1) demonstrated that differences in nucleic acid metabolism between cancerous cells and normal cells or between cells from different organisms led to the design and development of nucleic acid analogs that would effectively and selectively block nucleic acid synthesis in the desired target cells. Among the drugs that emanated from this work are 6-mercaptopurine (6-MP), 1 6-thioguanine (6-TG), azathioprine, allopurinol, and acyclovir (2, 3). These drugs are still in use for the treatment of leukemias (6-MP and 6-TG) and autoimmune disorders and the prevention of organ transplant rejection (azathioprine), gout (allopurinol), and herpes virus infections (acyclovir). Additional nucleic acid anti-metabolites that were developed are effective in bacterial infections and malaria.The clinical efficacy of 6-MP is due in part to antiproliferative and cytotoxic effects resulting primarily from the inhibition of purine biosynthesis at multiple steps and incorporation into nucleic acids as thioguanine nucleotides (2-7). More recent work has expanded the function of purine anti-metabolites by demonstrating that compounds such as 6-thioguanine or 6-mercaptopurine can target biological activities outside of the purine biosynthesis pathway including telomerase (5), protein kinase N (6, 7), axon growth and regeneration (8, 9), and apoptosis in B cells through the regulation of the Bcl-2/Bax ratio (10).In this study, we have identified, from a high throughput screen, 6-mercaptopurine as a regulator of the transcriptional activity of the orphan nuclear hormone receptor Nurr1. There are three members of the NGFI-B group, including Nurr1 ...

show abstract

Section: -Mercaptopurine Controls Nurr1 Transcription Activitysupporting

confidence: 80%

Section: -Mercaptopurine Activation Of Nurr1 Can Be Blocked By Replementioning

confidence: 99%

Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1

Ordentlich

Yan

Zhou

et al. 2003

Journal of Biological Chemistry

103

View full text Add to dashboard Cite

show abstract

“…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).…”

Section: Discussionmentioning

confidence: 98%

Purine metabolism and the microaerophily of Helicobacter pylori

Mendz

Shepley

Hazell

et al. 1997

Archives of Microbiology

View full text Add to dashboard Cite

The requirements for purine nucleotide synthesis, the effects of purine analogues, and the metabolism of adenine in the bacterium Helicobacter pylori were investigated employing cell culture techniques and one-dimensional NMR spectroscopy. Bacterial cells grew and proliferated in media lacking preformed purines, indicating that H. pylori can synthesize purine nucleotides de novo to meet its requirements. Blocking of this pathway in the absence of sufficient preformed purines for salvage nucleotide synthesis led to cell death. Analogues of purine nucleobases and nucleosides taken up by the cells were cytotoxic, suggesting that salvage routes could be exploited for therapy. Adenine or hypoxanthine were able to substitute for catalase in supporting cell growth and proliferation, suggesting a role for these bases in maintaining the microaerophilic conditions essentially required by the bacterium.

show abstract

“…These metabolites, which are collectively termed 6-thioguanine nucleotides (TGNs), interfere with normal DNA and RNA synthesis and are critical for the cytotoxic effects of 6MP[8]. 6MP can also be methylated by thiopurine methyltransferase (TPMT) to methylmercaptopurine[9–11] an inactive metabolite that cannot be converted to active nucleotides.…”

Section: -Mercaptopurinementioning

confidence: 99%

Pharmacogenomics in pediatric leukemia

Paugh

Stocco

Evans

2010

Current Opinion in Pediatrics

View full text Add to dashboard Cite

Purpose of review The therapeutic index of many medications, especially in children, is very narrow with substantial risk for toxicity at doses required for therapeutic effects. This is particularly relevant to cancer chemotherapy, where the risk of toxicity must be balanced against potential suboptimal (low) systemic exposure that can be less effective in patients with the higher rates of drug clearance. The purpose of this review is to discuss genetic factors that lead to interpatient differences in the pharmacokinetics and pharmacodynamics of these medications. Recent findings Genome wide agonistic studies of pediatric patient populations are revealing genome variations that may affect susceptibility to specific diseases and that influence the pharmacokinetic and pharmacodynamic characteristics of medications. Several genetic factors with relatively small effect may be combined in the determination of a pharmacogenomic phenotype and considering these polygenic models may be mandatory in order to predict the related drug response phenotypes. These findings have potential to yield new insights into disease pathogenesis, and lead to molecular diagnostics that can be used to optimize the treatment of childhood cancers Summary Advances in genome technology and their comprehensive and systematic deployment to elucidate the genomic basis of inter-patient differences in drug response and disease risk, hold great promise to ultimately enhance the efficacy and reduce the toxicity of drug therapy in children.

show abstract

Reversal of methylmercaptopurine ribonucleoside cytotoxicity by purine ribonucleosides and adenine

Cited by 25 publications

References 22 publications

Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1

Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1

Purine metabolism and the microaerophily of Helicobacter pylori

Pharmacogenomics in pediatric leukemia

Contact Info

Product

Resources

About