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01-08-2010 | Original Article

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

Authors: Rikke L. Hedeland, Kristian Hvidt, Jacob Nersting, Susanne Rosthøj, Kim Dalhoff, Birgitte Lausen, Kjeld Schmiegelow

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2010

Abstract

Purpose

To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT).

Methods

We studied these metabolites in 229 blood samples from 18 children with ALL (N = 16) or NHL (N = 2) on 6MP/Methotrexate maintenance therapy.

Results

DNA-6TGN levels were significantly correlated to E-6TGN (r _p = 0.66, p = 0.003) with a trend to reach a plateau at high E-6TGN levels. To explore the relative DNA incorporation of 6TGN in relation to cytosol 6TGN levels, a DNA-6TGN index was calculated as DNA-6TGN/E-6TGN. The DNA-6TGN index was inversely correlated to E-6TGN (r _p = −0.58, p = 0.012), which implies that with increasing levels of E-6TGN relatively less 6TGN are incorporated into DNA. E-MeMP levels were correlated to the DNA-TGN index (r _p = 0.60, p = 0.008), indicating that high levels of MeMP result in enhanced DNA-6TGN incorporation, possibly due to inhibition of purine de novo synthesis, mediated by some of the methylated 6MP metabolites.

Conclusions

DNA-6TGN may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than the previously used erythrocyte 6MP metabolites levels. Prospective clinical trials are needed to evaluate the usefulness of DNA-6TGN for individual dose adjustments.

Schmiegelow K, Gustafsson G (2005) Acute lymphoblastic leukemia. In: Caron M (ed) Cancer in children. Oxford University Press, Oxford, pp 138–170

Schmiegelow K, Pulczynska MK (1990) Maintenance chemotherapy for childhood acute lymphoblastic leukemia: should dosage be guided by white blood cell counts? Am J Pediatr Hematol Oncol 12:462–467CrossRefPubMed

Arico M, Baruchel A, Bertrand Y, Biondi A, Conter V, Eden T, Gadner H, Gaynon P, Horibe K, Hunger SP, Janka-Schaub G, Masera G, Nachman J, Pieters R, Schrappe M, Schmiegelow K, Valsecchi MG, Pui CH (2005) The seventh international childhood acute lymphoblastic leukemia workshop report: Palermo, Italy, January 29–30, 2005. Leukemia 19:1145–1152CrossRefPubMed

Uribe-Luna S, Quintana-Hau JD, Maldonado-Rodriguez R, Espinosa-Lara M, Beattie KL, Farquhar D, Nelson JA (1997) Mutagenic consequences of the incorporation of 6-thioguanine into DNA. Biochem Pharmacol 54:419–424CrossRefPubMed

Bokkerink JP, Stet EH, De Abreu RA, Damen FJ, Hulscher TW, Bakker MA, van Baal JA (1993) 6-Mercaptopurine: cytotoxicity and biochemical pharmacology in human malignant T-lymphoblasts. Biochem Pharmacol 45:1455–1463CrossRefPubMed

Schmiegelow K, Forestier E, Kristinsson J, Soderhall S, Vettenranta K, Weinshilboum R, Wesenberg F (2009) Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia 23:557–564CrossRefPubMed

Wang L, Weinshilboum R (2006) Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions. Oncogene 25:1629–1638CrossRefPubMed

Lilleyman JS, Lennard L (1994) Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. Lancet 343:1188–1190CrossRefPubMed

Erb N, Harms DO, Janka-Schaub G (1998) Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol 42:266–272CrossRefPubMed

10.

Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE (1999) Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 93:2817–2823PubMed

11.

Schmiegelow K, Schroder H, Gustafsson G, Kristinsson J, Glomstein A, Salmi T, Wranne L (1995) Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology. J Clin Oncol 13:345–351PubMed

12.

Lennard L (2001) Therapeutic drug monitoring of cytotoxic drugs. Br J Clin Pharmacol 52:75–87CrossRef

13.

Gustafsson G, Schmiegelow K, Forestier E, Clausen N, Glomstein A, Jonmundsson G, Mellander L, Makipernaa A, Nygaard R, Saarinen-Pihkala UM (2000) Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate in the reduction of CNS irradiation. Nordic Society of Pediatric Haematology and Oncology (NOPHO). Leukemia 14:2267–2275CrossRefPubMed

14.

Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215CrossRefPubMed

15.

Bruunshuus I, Schmiegelow K (1989) Analysis of 6-mercaptopurine, 6-thioguanine nucleotides, and 6-thiouric acid in biological fluids by high-performance liquid chromatography. Scand J Clin Lab Invest 49:779–784CrossRefPubMed

16.

Erdmann GR, Steury JC, Carleton BC, Stafford RJ, Bostrom BC, Canafax DM (1991) Reversed-phase high-performance liquid chromatographic approach to determine total lymphocyte concentrations of 6-thioguanine, methylmercaptopurine and methylthioguanine in humans. J Chromatogr 571:149–156CrossRefPubMed

17.

Kamen BA, Takach PL, Vatev R, Caston JD (1976) A rapid, radiochemical-ligand binding assay for methotrexate. Anal Biochem 70:54–63CrossRefPubMed

18.

Siegel S, Castellan NJ (1988) Non-parametric statistics for the behavioral science. McGraw-Hill, Singapore

19.

Cleveland WS, Devlin SJ (1988) Locally weighted regression: an approach to regression analysis by local fitting. J Am Stat Assoc 83:596–610CrossRef

20.

Peeters M, Koren G, Jakubovicz D, Zipursky A (1988) Physician compliance and relapse rates of acute lymphoblastic leukemia in children. Clin.Pharmacol Ther 43:228–232PubMed

21.

Lancaster D, Lennard L, Lilleyman JS (1997) Profile of non-compliance in lymphoblastic leukaemia. Arch Dis Child 76:365–366CrossRefPubMed

22.

Lennard L, Van Loon JA, Weinshilboum RM (1989) Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46:149–154PubMed

23.

Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91:2001–2008CrossRefPubMed

24.

Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM (2004) Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin Gastroenterol Hepatol 2:410–417CrossRefPubMed

25.

Schmiegelow K, Bjork O, Glomstein A, Gustafsson G, Keiding N, Kristinsson J, Makipernaa A, Rosthoj S, Szumlanski C, Sorensen TM, Weinshilboum R (2003) Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol 21:1332–1339CrossRefPubMed

26.

Krynetski EY, Tai HL, Yates CR, Fessing MY, Loennechen T, Schuetz JD, Relling MV, Evans WE (1996) Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6:279–290CrossRefPubMed

27.

Andersen JB, Szumlanski C, Weinshilboum RM, Schmiegelow K (1998) Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 87:108–111CrossRefPubMed

28.

Bo J, Schroder H, Kristinsson J, Madsen B, Szumlanski C, Weinshilboum R, Andersen JB, Schmiegelow K (1999) Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism. Cancer 86:1080–1086CrossRefPubMed

29.

Schmiegelow K, Al-Modhwahi I, Andersen MK, Behrendtz M, Forestier E, Hasle H, Heyman M, Kristinsson J, Nersting J, Nygaard R, Svendsen AL, Vettenranta K, Weinshilboum R (2009) Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Blood 113:6077–6084CrossRefPubMed

30.

Harms DO, Gobel U, Spaar HJ, Graubner UB, Jorch N, Gutjahr P, Janka-Schaub GE (2003) Thioguanine offers no advantage over mercaptopurine in maintenance treatment of childhood ALL: results of the randomized trial COALL-92. Blood 102:2736–2740CrossRefPubMed

31.

Vora A, Mitchell CD, Lennard L, Eden TO, Kinsey SE, Lilleyman J, Richards SM (2006) Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 368:1339–1348CrossRefPubMed

Title: DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma
Authors: Rikke L. Hedeland
Kristian Hvidt
Jacob Nersting
Susanne Rosthøj
Kim Dalhoff
Birgitte Lausen
Kjeld Schmiegelow
Publication date: 01-08-2010
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1184-5

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