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Chemical Compound Review:

AC1NV8O5 3,5-dihydropurine-6-thione

Synonyms:

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Disease relevance of Leukeran

Polymorphisms at three loci in the thiopurine methyltransferase (TPMT) gene are known to be responsible for azathioprine and 6-mercaptopurine (6MP) toxicity [1].
METHODS: Patients with inflammatory bowel disease who had been treated with azathioprine or MP in Christchurch between 1996 and 2002 were identified [2].
PURPOSE: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL [3].

High impact information on Leukeran

Murine embryonic fibroblasts (MEFs) from Msh2+/+ mice also exhibited increased sensitivity to MP when compared with MEFs from Msh2-/- mice (IC50, 3.8 +/- 0.1 microM versus 11.9 +/- 1.3 microM, p < 0.001) [4].
After MP treatment, deoxythioguanosine incorporation into DNA was similar in mice and MEFs with each of the Msh2 genotypes [4].
Incubation with 6MP led to the formation of thioinosine and thioxanthosine metabolites and we found that thio-IMP was transported by both MRP4 and MRP5; MRP5 showed the highest transport rate [5].
Redistribution of GAPDH from cytosol to nucleus was evident after MP treatment [6].
The immunosuppressive efficacy of azathioprine is related to its rapid metabolism in vivo to 6-mercaptopurine (6MP), with subsequent conversion to thioguanine nucleotides by an anabolic route involving hypoxanthine-guanine phosphoribosyltransferase [7].

Biological context of Leukeran

As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL [3].
Synthesis, characterization and hydrolysis in aqueous buffers of novel N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of substituted phenols, theophylline (Th) and 6-mercaptopurine (6MP) were carried out [8].
In this article the genetic polymorphism of TPMT is reviewed and the contribution of TPMT to the cytotoxic action, or detoxification, of 6MP in children with ALL is discussed [9].

Anatomical context of Leukeran

Red blood cells can not be used for TPMT measurements, since transfusions are frequently required during the treatment with 6MP infusions [9].

Associations of Leukeran with other chemical compounds

In concordance with other authors, we found a higher TPMT activity during maintenance treatment with 6-mercaptopurine (6MP) than at diagnosis and in controls [10].
Topical delivery of selected derivatives of acetaminophen (APAP), Th and 6MP was examined in in vitro diffusion cell experiments from IPM across hairless mice skins [8].

Gene context of Leukeran

The number of weeks when 6MP therapy was administered at full dose was determined in patients on MRC UKALL X and XI [11].

Analytical, diagnostic and therapeutic context of Leukeran

Recent identification of the molecular basis for low TPMT activity enabled rapid assessment of altered 6MP metabolism by PCR methods [11].

References

Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Kumagai, K., Hiyama, K., Ishioka, S., Sato, H., Yamanishi, Y., McLeod, H.L., Konishi, F., Maeda, H., Yamakido, M. Pharmacogenetics (2001) [Pubmed]
Thiopurine S-methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease. Gearry, R.B., Barclay, M.L., Burt, M.J., Collett, J.A., Chapman, B.A., Roberts, R.L., Kennedy, M.A. Aliment. Pharmacol. Ther. (2003) [Pubmed]
Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia: a collaborative Pediatric Oncology Branch, NCI, and Children's Cancer Group study. Lowe, E.S., Kitchen, B.J., Erdmann, G., Stork, L.C., Bostrom, B.C., Hutchinson, R., Holcenberg, J., Reaman, G.H., Woods, W., Franklin, J., Widemann, B.C., Balis, F.M., Murphy, R.F., Adamson, P.C. Cancer Chemother. Pharmacol. (2001) [Pubmed]
Msh2 deficiency attenuates but does not abolish thiopurine hematopoietic toxicity in msh2-/- mice. Krynetskaia, N.F., Brenner, T.L., Krynetski, E.Y., Du, W., Panetta, J.C., Ching-Hon, P., Evans, W.E. Mol. Pharmacol. (2003) [Pubmed]
Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Wielinga, P.R., Reid, G., Challa, E.E., van der Heijden, I., van Deemter, L., de Haas, M., Mol, C., Kuil, A.J., Groeneveld, E., Schuetz, J.D., Brouwer, C., De Abreu, R.A., Wijnholds, J., Beijnen, J.H., Borst, P. Mol. Pharmacol. (2002) [Pubmed]
A novel protein complex distinct from mismatch repair binds thioguanylated DNA. Krynetski, E.Y., Krynetskaia, N.F., Gallo, A.E., Murti, K.G., Evans, W.E. Mol. Pharmacol. (2001) [Pubmed]
The importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients. Chocair, P.R., Duley, J.A., Simmonds, H.A., Cameron, J.S. Transplantation (1992) [Pubmed]
Synthesis, hydrolyses and dermal delivery of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of phenol, imide and thiol containing drugs. Majumdar, S., Sloan, K.B. Bioorg. Med. Chem. Lett. (2006) [Pubmed]
Thiopurine methyltransferase: a review and a clinical pilot study. Keuzenkamp-Jansen, C.W., Leegwater, P.A., De Abreu, R.A., Lambooy, M.A., Bokkerink, J.P., Trijbels, J.M. J. Chromatogr. B, Biomed. Appl. (1996) [Pubmed]
Thiopurine methyltransferase in acute lymphoblastic leukaemia: biochemical and molecular biological aspects. Brouwer, C., De Abreu, R.A., Keizer-Garritsen, J.J., Lambooy, L.H., Ament, K., ter Riet, P.G., van Wering, E.R., Trijbels, F.J., Veerman, A.J., Hoogerbrugge, P.M., Bökkerink, J.P. Eur. J. Cancer (2005) [Pubmed]
Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. McLeod, H.L., Coulthard, S., Thomas, A.E., Pritchard, S.C., King, D.J., Richards, S.M., Eden, O.B., Hall, A.G., Gibson, B.E. Br. J. Haematol. (1999) [Pubmed]

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