Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia

English version

Autoři: Natanja Oosterom ^aff001; Robert de Jonge ^aff003; Desiree E. C. Smith ^aff003; Rob Pieters ^aff001; Wim J. E. Tissing ^aff001; Marta Fiocco ^aff001; Bertrand D. van Zelst ^aff002; Marry M. van den Heuvel-Eibrink ^aff001; Sandra G. Heil ^aff002
Působiště autorů: Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands ^aff001; Erasmus MC, University Medical Center Rotterdam, Department of Clinical Chemistry, Rotterdam, The Netherlands ^aff002; VU Medical Center, Department of Clinical Chemistry, Amsterdam, The Netherlands ^aff003; Academic Medical Center, Department of Clinical Chemistry, Amsterdam, The Netherlands ^aff004; Department of Pediatric Oncology, University of Groningen, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands ^aff005; Mathematical Institute, Leiden University, Leiden, The Netherlands ^aff006; Leiden University Medical Center, Department of Biomedical Data Sciences, Leiden, The Netherlands ^aff007
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0221591

Souhrn

Background

Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could ‘rescue’ both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX.

Methods

We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses.

Results

Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, p<0.001). This was due to an increase in 5-methyl THF levels (mean increase: 217.7 ± 209.5 nmol/L, p<0.001), whereas non-methyl THF levels did not change (median increase: 0.6 nmol/L [-9.9–11.1], p = 0.676). Serum folate levels increased between T0 and T1 (median increase: 29.2 nmol/L [32.9–74.0], p<0.001). Results were not significantly affected by age, sex, ALL immunophenotype and MTHFR c.677C>T genotype.

Conclusion

Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.

Klíčová slova:

Biology and life sciences – Cell biology – Physical sciences – Chemistry – Cellular types – Animal cells – Anatomy – Medicine and health sciences – Chemical compounds – Physiology – Organic compounds – Organic chemistry – Pediatrics – Pharmacology – Vitamins – Body fluids – Blood – Blood plasma – Oncology – Cancer treatment – Cancers and neoplasms – Hematologic cancers and related disorders – Hematology – Drugs – Blood cells – B vitamins – Red blood cells – Leukemias – Lymphoblastic leukemia – Acute lymphoblastic leukemia – Methotrexate – Cobalamins

Zdroje

1. Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, et al. Childhood cancer survival in Europe 1999–2007: results of EUROCARE-5—a population-based study. The Lancet Oncology 2014;15:35–47 doi: 10.1016/S1470-2045(13)70548-5 24314616

2. Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011;29:551–65

3. Kamps WA, van der Pal-de Bruin KM, Veerman AJ, Fiocco M, Bierings M, Pieters R. Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004. Leukemia 2010;24:309–19 doi: 10.1038/leu.2009.258 20016528

4. Funk RS, van Haandel L, Leeder JS, Becker ML. Folate depletion and increased glutamation in juvenile idiopathic arthritis patients treated with methotrexate. Arthritis & rheumatology (Hoboken, NJ) 2014;66:3476–85

5. Kao TT, Lee GH, Fu CC, Chen BH, Chen LT, Fu TF. Methotrexate-induced decrease in embryonic 5-methyl-tetrahydrofolate is irreversible with leucovorin supplementation. Zebrafish 2013;10:326–37 doi: 10.1089/zeb.2013.0876 23758124

6. Fiskerstrand T, Ueland PM, Refsum H. Folate depletion induced by methotrexate affects methionine synthase activity and its susceptibility to inactivation by nitrous oxide. The Journal of pharmacology and experimental therapeutics 1997;282:1305–11 9316839

7. Wennerstrand P, Martensson LG, Soderhall S, Zimdahl A, Appell ML. Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia. European journal of clinical pharmacology 2013;69:1641–9 doi: 10.1007/s00228-013-1521-9 23660772

8. Graham ML, Shuster JJ, Kamen BA, Cheo DL, Harrison MP, Leventhal BG, et al. Red blood cell methotrexate and folate levels in children with acute lymphoblastic leukemia undergoing therapy: a Pediatric Oncology Group pilot study. Cancer chemotherapy and pharmacology 1992;31:217–22 doi: 10.1007/bf00685551 1464159

9. Kamen BA, Holcenberg JS, Turo K, Whitehead VM. Methotrexate and folate content of erythrocytes in patients receiving oral vs intramuscular therapy with methotrexate. J Pediatr 1984;104:131 doi: 10.1016/s0022-3476(84)80610-1 6581287

10. Kamen BA, Nylan PA, Camitta BM, Bertino JR. Methotrexate accumulation and folate depletion in cells as a possible mechanism of chronic toxicity of the drug. British journal of haematology 1981;49:355 doi: 10.1111/j.1365-2141.1981.tb07237.x 6170307

11. Chan ES, Cronstein BN. Methotrexate—how does it really work? Nature reviews Rheumatology 2010;6:175–8 doi: 10.1038/nrrheum.2010.5 20197777

12. Goldman ID, Matherly LH. Biochemical factors in the selectivity of leucovorin rescue: selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates. NCI monographs: a publication of the National Cancer Institute 1987:17–26

13. Borsi JD, Wesenberg F, Stokland T, Moe PJ. How much is too much? Folinic acid rescue dose in children with acute lymphoblastic leukaemia. European journal of cancer (Oxford, England: 1990) 1991;27:1006–9

14. Wolfrom C, Hartmann R, Fengler R, Bruhmuller S, Ingwersen A, Henze G. Randomized comparison of 36-hour intermediate-dose versus 4-hour high-dose methotrexate infusions for remission induction in relapsed childhood acute lymphoblastic leukemia. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 1993;11:827–33

15. Skarby TV, Anderson H, Heldrup J, Kanerva JA, Seidel H, Schmiegelow K. High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia 2006;20:1955–62 doi: 10.1038/sj.leu.2404404 16990760

16. Sterba J, Dusek L, Demlova R, Valik D. Pretreatment plasma folate modulates the pharmacodynamic effect of high-dose methotrexate in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma: "folate overrescue" concept revisited. Clinical chemistry 2006;52:692–700 doi: 10.1373/clinchem.2005.061150 16455868

17. Tishler M, Caspi D, Fishel B, Yaron M. The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis and rheumatism 1988;31:906–8 doi: 10.1002/art.1780310712 3260783

18. Arabelovic S, Sam G, Dallal GE, Jacques PF, Selhub J, Rosenberg IH, et al. Preliminary evidence shows that folic acid fortification of the food supply is associated with higher methotrexate dosing in patients with rheumatoid arthritis. Journal of the American College of Nutrition 2007;26:453–5 17914133

19. Trevino LR, Shimasaki N, Yang W, Panetta JC, Cheng C, Pei D, et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2009;27:5972–8

20. Pauley JL, Panetta JC, Crews KR, Pei D, Cheng C, McCormick J, et al. Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments. Cancer chemotherapy and pharmacology 2013;72:369–78 doi: 10.1007/s00280-013-2206-x 23760811

21. Salzer WL, Winick NJ, Wacker P, Lu X, Devidas M, Shuster JJ, et al. Plasma methotrexate, red blood cell methotrexate, and red blood cell folate values and outcome in children with precursor B-acute lymphoblastic leukemia: a report from the Children's Oncology Group. Journal of pediatric hematology/oncology 2012;34:e1–7 doi: 10.1097/MPH.0b013e31820ee239 21364468

22. Wolfrom C, Hepp R, Hartmann R, Breithaupt H, Henze G. Pharmacokinetic study of methotrexate, folinic acid and their serum metabolites in children treated with high-dose methotrexate and leucovorin rescue. European journal of clinical pharmacology 1990;39:377–83 doi: 10.1007/bf00315414 2076721

23. Payet B, Fabre G, Tubiana N, Cano JP. Plasma kinetic study of folinic acid and 5-methyltetrahydrofolate in healthy volunteers and cancer patients by high-performance liquid chromatography. Cancer chemotherapy and pharmacology 1987;19:319–25 doi: 10.1007/bf00261481 3496173

24. Bunni MA, Rembiesa BM, Priest DG, Sahovic E, Stuart R. Accumulation of tetrahydrofolates in human plasma after leucovorin administration. Cancer chemotherapy and pharmacology 1989;23:353–7 doi: 10.1007/bf00435835 2785439

25. Smulders YM, Smith DE, Kok RM, Teerlink T, Gellekink H, Vaes WH, et al. Red blood cell folate vitamer distribution in healthy subjects is determined by the methylenetetrahydrofolate reductase C677T polymorphism and by the total folate status. The Journal of nutritional biochemistry 2007;18:693–9 doi: 10.1016/j.jnutbio.2006.11.010 17418558

26. Straw JA, Newman EM, Doroshow JH. Pharmacokinetics of leucovorin (D,L-5-formyltetrahydrofolate) after intravenous injection and constant intravenous infusion. NCI monographs: a publication of the National Cancer Institute 1987:41–5

27. Thyss A, Milano G, Etienne MC, Paquis P, Roche JL, Grelier P, et al. Evidence for CSF accumulation of 5-methyltetrahydrofolate during repeated courses of methotrexate plus folinic acid rescue. British journal of cancer 1989;59:627–30 doi: 10.1038/bjc.1989.127 2785400

28. Priest DG, Schmitz JC, Bunni MA, Stuart RK. Pharmacokinetics of leucovorin metabolites in human plasma as a function of dose administered orally and intravenously. Journal of the National Cancer Institute 1991;83:1806–12 doi: 10.1093/jnci/83.24.1806 1744924

29. van Ede AE, Laan RF, Blom HJ, Boers GH, Haagsma CJ, Thomas CM, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford, England) 2002;41:658–65

30. Refsum H, Wesenberg F, Ueland PM. Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate. Cancer research 1991;51:828–35 1988122

31. Kalhan SC, Marczewski SE. Methionine, homocysteine, one carbon metabolism and fetal growth. Reviews in endocrine & metabolic disorders 2012;13:109–19

32. Holmboe L, Andersen AM, Morkrid L, Slordal L, Hall KS. High dose methotrexate chemotherapy: pharmacokinetics, folate and toxicity in osteosarcoma patients. British journal of clinical pharmacology 2012;73:106–14 doi: 10.1111/j.1365-2125.2011.04054.x 21707700

33. Broxson EH, Jr., Stork LC, Allen RH, Stabler SP, Kolhouse JF. Changes in plasma methionine and total homocysteine levels in patients receiving methotrexate infusions. Cancer research 1989;49:5879–83 2790801

34. Strickland KC, Krupenko NI, Krupenko SA. Molecular mechanisms underlying the potentially adverse effects of folate. Clinical chemistry and laboratory medicine 2013;51:607–16 doi: 10.1515/cclm-2012-0561 23241610

35. Smulders YM, Smith DE, Kok RM, Teerlink T, Swinkels DW, Stehouwer CD, et al. Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap. British journal of haematology 2006;132:623–9 doi: 10.1111/j.1365-2141.2005.05913.x 16445837

36. Scott JM, Weir DG. The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet (London, England) 1981;2:337–40

37. den Hoed MA, Lopez-Lopez E, te Winkel ML, Tissing W, de Rooij JD, Gutierrez-Camino A, et al. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia. The pharmacogenomics journal 2015;15:248–54 doi: 10.1038/tpj.2014.63 25348617

38. Kabanova S, Kleinbongard P, Volkmer J, Andree B, Kelm M, Jax TW. Gene expression analysis of human red blood cells. International journal of medical sciences 2009;6:156–9 doi: 10.7150/ijms.6.156 19421340

39. Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, et al. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2016;34:2591–601

40. Smith DE, Kok RM, Teerlink T, Jakobs C, Smulders YM. Quantitative determination of erythrocyte folate vitamer distribution by liquid chromatography-tandem mass spectrometry. Clinical chemistry and laboratory medicine 2006;44:450–9 doi: 10.1515/CCLM.2006.085 16599840

41. Ducros V, Belva-Besnet H, Casetta B, Favier A. A robust liquid chromatography tandem mass spectrometry method for total plasma homocysteine determination in clinical practice. Clinical chemistry and laboratory medicine 2006;44:987–90 doi: 10.1515/CCLM.2006.178 16879066

42. den Boer E, Meesters RJ, van Zelst BD, Luider TM, Hazes JM, Heil SG, et al. Measuring methotrexate polyglutamates in red blood cells: a new LC-MS/MS-based method. Analytical and bioanalytical chemistry 2013;405:1673–81 doi: 10.1007/s00216-012-6581-7 23239179