Thiopurine induced disturbance of DNA methylation in human malignant cells

Abreu, Ronney A. De; Lambooy, Lambert H.J.; Stet, E. H.; Vogels-Mentink, Trude M.; Heuvel, Lambert van den

doi:10.1016/0065-2571(94)00008-q

Cited by 21 publications

(15 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Even without this knowl edge, the méthylation status might be a target for chemo therapeutic agents. In line with this view, we recently that incubation of Molt F4 lymphoblasts with 6MP resulted in changes in the concentrations of transmethylation metabolites [12] and in DNA méthyl ation [13].…”

Section: Discussionsupporting

confidence: 58%

“…Thus, the effects of 6MP and MeMPR on these transmethylation metabolites were ascribed to the reduced conversion of methionine into AdoMet, due to ATPdepletion produced by MetIMP [12]. More recently, we observed that incubation of Molt-F4 lymphoblasts with 6MP or MeMPR resulted in a decrease in the incorporation of [14C] from [14C]-methionine into total DNA [13], sug gesting that thiopurines can influence DNA méthylation in vitro.…”

mentioning

confidence: 74%

See 1 more Smart Citation

Effects on transmethylation by high-dose 6-mercaptopurine and methotrexate infusions during consolidation treatment of acute lymphoblastic leukemia

Keuzenkamp-Jansen

Abreu

Blom

et al. 1996

Biochemical Pharmacology

View full text Add to dashboard Cite

']a r is e n R o n n e y A. De Ahreu,*f HenkJ. Blom* Jos P.M. Bokkerinkf andj. M. Frans Trijbels* ♦ L a b o r a t o r y o f P e d i a t r i c s , a n d t C e n t e r f o r P e d ia t r ic : O n c o l o g y S.E. N e t h e r l a n d s , U n i v e r s i t y H o s p i t a l S t . R a d b o u d , P.O. Box 9101» 6500 HB N ijm e g e n , T h e N e t h e r l a n d s A BSTRA CT. 6 -mercaptopurine (6MP) cytotoxicity is caused by thioguanine and methylthioinosine nucleo tides. Thiopurine méthylation occurs to a large extent in vivo and in vitro. In this reaction, S-adenosyl-Lmethionine (AdoMet), produced from methionine and ATP, is converted into S-adenusy l-L-htunocysreine (AdoHcy) which, in turn, is hydrolyzed into homocysteine. Remethylation of homocysteine into methionine is inhibited by methotrexate (MTX). In cultured lymphoblasts, AdoMenAdoHcy ratio and DNA méthylation decrease after incubation with 6MP. The aim of the present study was to investigate the influence of high-do.se 6MP on the méthylation capacity in children with acute lymphoblastic leukemia. Five patients received 4 courses with high-dose intravenous MTX (5 g • m in 24 hr) immediately followed by high-dose 6MP (1300 mg • m~2 in 24 hr). Five control patients received high-dose MTX and oral 6MP (25 mg • m~2 daily for 8 weeks). Leucovorin rescue was started at .36 hr in both groups.In the intravenous 6MP group, 6-methylmercaptopurine, its riboside, and 6-methylmercapto-8-hydroxypurine were detectable in plasma in concentrations of 0.3-2.6 |jlM (6MP steady state levels: 11.6 (xM). In red blood cells, mean methylthioinosine nucleotide levels were one third of those of ATP (13,1 nmol/10"). AdoHcy levels (10 pmol/108) remained constant in both groups and AdoMet was not detectable (<20 pmol/10,s). In both groups, plasma homocysteine increased and methionine decreased following administration of MTX. The delay in the recovery of methionine in the intravenous 6MP group after MTX infusion is probably the result-of an increased demand on methyl groups during 6MP infusion. BIOCHKM PHARMACOL 51;9:1165-1171, KEY W ORDS. 6 -mercaptopurine; methotrexate; acute lymphoblastic leukemia; méthylation § is used in the treatment of ALL. It has no intrinsic cytotoxic activity, but is converted into active metabolites intracellularly (Scheme 1). 6MP tlMP which, itself, can be conve MetlMP. Both pathways ferase (EC 2.1.1.67) (TPMT). The TPMT activity is con trolled by a genetic polymorphism and the activity in RBC correlates with that in lymphoblasts, lymphocytes, plate lets, liver, and ki •' V ** % oi in cytotoxicity in vitro, ei ther by incorporation of thioguanine nucleotides into DNA and RNA [1,2] or by inhibition of purine de novo synthesis by MetlMP [2,3]. 6MP is methylated into MeMP and 6MP-riboside into MeMPR (Scheme 1). The thiopurine meththe frequency distribution is trimodal with subjects displaying high activity, 11.1% intermediate activ ity, and 1 out of 300 subjects having undeteetahle TPMT . Thiopurine méthylation requires AdoMet as onor [9]. AdoMet is the universa...

show abstract

Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 74%

Effects on transmethylation by high-dose 6-mercaptopurine and methotrexate infusions during consolidation treatment of acute lymphoblastic leukemia

Keuzenkamp-Jansen

Abreu

Blom

et al. 1996

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…9,10 Further more, it have been suggested that immunosuppressive drugs are related to carcinogenesis. [11][12][13] It has been reported that, when immunosuppressive drugs were used for rheumatoid arthritis and renal transplants, that non-Hodgkin's lymphoma, skin cancer, and HCC developed, and this possibility does have to be weighed against the clinical benefits of such drugs. 14 Our patient was negative for HBV and HCV, and the background risk of carcinogenesis in his IBD seemed to be associated with immunosuppressive therapy.…”

Section: Discussionmentioning

confidence: 98%

Development of hepatocellular carcinoma following treatment with6-mercaptopurine for ulcerative colitis: investigation of chromosomal aberration by comparative genomic hybridization

et al. 2005

View full text Add to dashboard Cite

In a 64-year-old man who had been treated with prednisolone (PSL) and 6-mercaptopurine (6MP) for a long period, for ulcerative colitis (UC), hepatocellular carcinoma (HCC) was detected incidentally. The UC was in remission with these medications. After he had been taking these medications for about 8 years, HCC was detected by computed tomography (CT), done for the evaluation of an other disease. Blood chemistry examination results were normal, except that the protein induced by vitamin K antagonist (PIVKA)-II level was 7940 AU/ml. We performed resection of liver segment V. With comparative genomic hybridization, chromosomal aberrations were recognized; these were gains of 1q, 3ptel-21, 8p12, and 22q11.23-22q13.1. Generally, HCC is associated with hepatitis virus infection in most cases, but in this patient, the HCC was not related to hepatitis C virus (HCV) or HBV. It is presumed that this case was related to the immunosuppressive therapy for UC and was associated with the gains of 1q, 3p, and 8p.

show abstract

“…B 6 7 8 ( 1 9 9 6 6 MP(R), 6 -mereaptopurine-(riboside); ()McMP(R), 6 -mcthylmereaptopurme-(riboside); (Me)tlMP, 6 -<uielhy 1 )thioinosi ne monophosphate; tGMP, 6 -thioguanosine monophosphate; PDNS, de novo synthesis of the purine. (l) thiopurine methyltransfcrase; (2 ) hypoxanthine guanine phosphoribosyltrans(erase; (3) purine nucleoside phosphorylase; (4) purine 5'-nueleotidase; (5) adenosine kinase; (6 ) inosine monophosphute dehydrogenase; (7) guanosine monophos phate synthetase; (8 ) guanosine monophosphate reductase; (9) xanthine oxidase.…”

Section: Involvement Of Thiopurine Methyltransferase In the Metabolismentioning

confidence: 99%

“…The importance of each cytotoxic pathway in vivo is discussed in scction 3. Apart from a decrease in the synthesis of DNA and RNA [5], inhibition of the de novo synthesis of the purine can also lead to a decrease of intracellular S-Adenosyl-L-methionine [8] and of DNA methylation [9] in vitro, S-Adenosyl-Lmethionine is the methyl donor for thiopurine meth ylation reactions [10] and for other methylation reactions» e.g. proteins, phospholipids and nucleic acids [11].…”

Section: Involvement Of Thiopurine Methyltransferase In the Metabolismentioning

confidence: 99%

Thiopurine methyltransferase: a review and a clinical pilot study

Keuzenkamp-Jansen

Leegwater

Abreu

et al. 1996

Journal of Chromatography B: Biomedical Sciences and Applicatio

View full text Add to dashboard Cite

Thiopurine methyltransferase (TPMT) is an important enzyme in the metabolism of 6-mercaptoptirine (6MP), which is used in the treat men t of acute lymphoblastic leukemia (ALL). TPMT catalyzes the formation of methylthioi nosine monophosphate (MetlMP), which is cytotoxic for cultured cell lines, and it plays a role in detoxification of 6MP, Population studies show a genetic polymorphism for TPMT with both high and low activity alleles. About 1 of 300 subjects is homozygous for the low activity. The function TPMT plays in detoxification or therapeutic efficacy of 6MP in vivo is not clear. 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. Induction of TPMT activity has been described during the treatment for ALL. We performed a pilot study on the influence of higlvdose 6MP infusions (1300 m g/m 2 in 24 h) on TPMT activity of peripheral blood mononuclear cells (pMNC) of eleven patients with ALL. The TPMT activities were in, or, above the normal range. There was no statistically significant difference between the TPMT activities before and after the 6MP infusions. MetlMP levels in pMNC increased during successive courses. This might be explained by TPMT induction, but other explanations are plausible as well. Twenty five percent of the TPMT assays failed, because less than the necessary 5*i0f' pMNC could be isolated from the blood of leukopenic patients. Red blood cells can not be used for TPMT measurements, since transfusions are frequently required during the treatment with 6MP infusions. Therefore, the influence of high-dose 6MP infusions on TPMT activity can only be investigated further when a TPMT assay which requires less pMNC has been developed.

show abstract

Thiopurine induced disturbance of DNA methylation in human malignant cells

Cited by 21 publications

References 33 publications

Effects on transmethylation by high-dose 6-mercaptopurine and methotrexate infusions during consolidation treatment of acute lymphoblastic leukemia

Effects on transmethylation by high-dose 6-mercaptopurine and methotrexate infusions during consolidation treatment of acute lymphoblastic leukemia

Development of hepatocellular carcinoma following treatment with6-mercaptopurine for ulcerative colitis: investigation of chromosomal aberration by comparative genomic hybridization

Thiopurine methyltransferase: a review and a clinical pilot study

Contact Info

Product

Resources

About