70 let methotrexátu v léčbě autoimunitních a nádorových onemocnění

Methotrexát byl před 70 lety zaveden do klinické praxe pro svou imunosupresivní a protinádorovou aktivitu. Přestože jsou neustále vyvíjena nová chemoterapeutika a imunomodulátory včetně antifolátových léčiv zůstává methotrexát zlatým standardem v terapii revmatoidní artritidy a některých maligních onemocnění. Methotrexát je dlouhodobě znám jako kompetitivní inhibitor enzymu dihydrofolátreduktasy, což je jeho hlavní mechanismus účinku. Byly popsány další farmakodynamické účinky a aktuálním předmětem zkoumání jsou mechanismy účinku nezávislé na inhibici tohoto enzymu. Při léčbě revmatoidní artritidy methotrexát snižuje hladiny významných mediátorů zánětu, jako jsou polyaminy a leukotrien-B4. Methotrexát snižuje expresi genů Jun N-terminální kinázy a B-cell lymfomu 2. Jeho endogenními metabolity jsou 7-hydroxymethotrexát, který vzniká jaterní biotransformací parentální sloučeniny a intracelulárně syntetizované polyglutamátové formy. Metabolity methotrexátu jsou farmakologicky aktivní a mají rozdílnou inhibiční aktivitu vůči dihydrofolátreduktase. V tomto přehledovém článku shrnujeme aktuální poznatky o léčivu v onkologické a revmatologické terapii a diskutujeme nové potenciální biomarkery toxicity, jejichž monitorování by mohlo zlepšit zavedené terapeutické protokoly.

Klíčová slova:
methotrexát, autoimunitní onemocnění, nádory, biologické markery, toxicita, nežádoucí účinky

Autoři: M. Řiháček ^1,2; I. Řiháček ^1,3; L. Zdražilová-Dubská ^1,2,4; K. Pilátová ^1,2
Působiště autorů: Faculty of Medicine, Masaryk University, Kamenice, Brno, Czech RepublicHead prof. MUDr. J. Mayer, CSc. ¹; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech RepublicHead doc. MUDr. D. Valík, Ph. D. ²; Department of Pharmacology – ACIU, Faculty of Medicine, Masaryk University, Kamenice, Brno, Czech RepublicHead MUDr. R. Demlová, Ph. D. ⁴; nd Department of Internal Medicine, St. Anne’s University Hospital, Brno. Czech RepublicHead prof. MUDr. M. Souček, CSc. ³²
Vyšlo v časopise: Čes-slov Pediat 2014; 69 (3): 161-167.
Kategorie: Přehledový článek

Souhrn

Klíčová slova:
methotrexát, autoimunitní onemocnění, nádory, biologické markery, toxicita, nežádoucí účinky

Zdroje

1. Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid, 4-Aminopteroyl-Glutamic Acid (Aminopterin). N Engl J Med 1948; 23: 787–793.

2. Ward JR. Historical perspective on the use of methotrexate for the treatment of rheumatoid arthritis. J Rheumatol 1985; Suppl: 3–6.

3. Drugs.com. Methotrexate. http://www.drugs.com/methotrexate.html. Accessed January 31, 2014.

4. Valik D, Radina M, Sterba J, et al. Homocysteine: Exploring its potential as a pharmacodynamic biomarker of antifolate chemotherapy. Pharmacogenomics 2004; 8: 1151–1162.

5. Chan ES, Cronstein BN. Methotrexate – how does it really work? Nat Rev Rheumatol 2010; 3: 175–178.

6. Cutolo M, Sulli A, Pizzorni C, et al. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 2001; 8: 729–735.

7. Genestier L, Paillot R, Fournel S, et al. Immu-nosuppressive properties of methotrexate: Apoptosis and clonal deletion of activated peripheral t cells. J Clin Invest 1998; 2: 322–328.

8. Johnston A, Gudjonsson JE, Sigmundsdottir H, et al. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol 2005; 2: 154–163.

9. Sperling RI, Benincaso AI, Anderson RJ, et al. Acute and chronic suppression of leukotriene b4 synthesis ex vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate. Arthritis Rheum 1992; 4: 376–384.

10. Lammers AM, van de Kerkhof PC, Mier PD. Reduction of leukotriene b4-induced intraepidermal accumulation of polymorphonuclear leukocytes by methotrexate in psoriasis. Br J Dermatol 1987; 5: 667–671.

11. Crooks SW, Stockley RA. Leukotriene b4. Int J Bio-chem Cell Biol 1998; 2: 173–178.

12. Nesher G, Osborn TG, Moore TL. In vitro effects of methotrexate on polyamine levels in lymphocytes from rheumatoid arthritis patients. Clin Exp Rheumatol 1996; 4: 395–399.

13. Nesher G, Osborn TG, Moore TL. Effect of treatment with methotrexate, hydroxychloroquine, and prednisone on lymphocyte polyamine levels in rheumatoid arthritis: Correlation with the clinical response and rheumatoid factor synthesis. Clin Exp Rheumatol 1997; 4: 343–347.

14. Spurlock CF 3rd, Aune ZT, Tossberg JT, et al. Increased sensitivity to apoptosis induced by methotrexate is mediated by jnk. Arthritis Rheum 2011; 9: 2606–2616.

15. Cho HW, Park SK, Heo KW, et al. Methotrexate induces apoptosis in nasal polyps via caspase cascades and both mitochondria-mediated and p38 mitogen-activated protein kinases/jun n-terminal kinase pathways. Am J Rhinol Allergy 2013; 1: e26–31.

16. Florou D, Patsis C, Ardavanis A, et al. Effect of doxorubicin, oxaliplatin, and methotrexate administration on the transcriptional activity of bcl-2 family gene members in stomach cancer cells. Cancer Biol Ther 2013; 7: 587–596.

17. Floros KV, Talieri M, Scorilas A. Topotecan and methotrexate alter expression of the apoptosis-related genes bcl2, fas and bcl2l12 in leukemic hl-60 cells. Biol Chem 2006; 12: 1629–1633.

18. Trevino LR, Shimasaki N, Yang W, et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol 2009; 35: 5972–5978.

19. Rau T, Erney B, Gores R, et al. High-dose methotrexate in pediatric acute lymphoblastic leukemia: Impact of abcc2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 2006; 5: 468–476.

20. Westerhof GR, Schornagel JH, Kathmann I, et al. Carrier- and receptor-mediated transport of folate antagonists targeting folate-dependent enzymes: Correlates of molecular-structure and biological activity. Mol Pharmacol 1995; 3: 459–471.

21. Jolivet J, Chabner BA. Intracellular pharmacokinetics of methotrexate polyglutamates in human breast cancer cells. Selective retention and less dissociable binding of 4-nh2-10-ch3-pteroylglutamate4 and 4-nh2-10-ch3-pteroylglutamate5 to dihydrofolate reductase. J Clin Invest 1983; 3: 773–778.

22. Chabner BA, Allegra CJ, Curt GA, et al. Poly-glutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest 1985; 3: 907–912.

23. Hobl EL, Jilma B, Erlacher L, et al. A short-chain methotrexate polyglutamate as outcome parameter in rheumatoid arthritis patients receiving methotrexate. Clin Exp Rheumatol 2012; 2: 156–163.

24. den Boer E, Meesters RJ, van Zelst BD, et al. Measuring methotrexate polyglutamates in red blood cells: A new lc-ms/ms-based method. Anal Bioanal Chem 2013; 5: 1673–1681.

25. Li H, Luo W, Zeng Q, et al. Method for the determination of blood methotrexate by high performance liquid chromatography with online post-column electrochemical oxidation and fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 1: 164–168.

26. Pavelka K, Venclovsky J. Doporučení české revmatologické společnosti pro léčbu revmatoidní artritidy. Čes Revmatol 2010; 4: 182–191.

27. Farmakoterapie psoriázy. Farmakoterap Inform 2011; 2: 1–3.

28. Schmiegelow K, Bjork O, Glomstein A, et al. Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol 2003; 7: 1332–1339.

29. Schmiegelow K, Heyman M, Kristinsson J, et al. Oral methotrexate/6-mercaptopurine may be superior to a multidrug lsa2l2 maintenance therapy for higher risk childhood acute lymphoblastic leukemia: Results from the nopho all-92 study. J Pediatr Hematol Oncol 2009; 6: 385–392.

30. Moricke A, Reiter A, Zimmermann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: Treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial all-bfm 95. Blood 2008; 9: 4477–4489.

31. Jaffe N, Gorlick R. High-dose methotrexate in osteosarcoma: Let the questions surcease--time for final acceptance. J Clin Oncol 2008; 27: 4365–4366.

32. Woessmann W, Seidemann K, Mann G, et al. The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with b-cell neoplasms: A report of the bfm group study nhl-bfm95. Blood 2005; 3: 948–958.

33. Baggott JE, Morgan SL. Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation. Arthritis Rheum 2009; 8: 2257–2261.

34. Fabre G, Seither R, Goldman ID. Hydroxylation of 4-amino-antifolates by partially purified aldehyde oxidase from rabbit liver. Biochem Pharmacol 1986; 8: 1325–1330.

35. Farquhar D, Loo TL. Synthesis and biologic evaluation of 7-hydroxymethotrexate, 7-methylaminopterin, and 7-methylmethotrexate. J Med Chem 1972; 5: 567–569.

36. Erttmann R, Bielack S, Landbeck G. 7-hydroxy-methotrexate and clinical toxicity following high-dose methotrexate therapy. J Cancer Res Clin Oncol 1985; 1: 86–88.

37. Schnabel A, Gross WL. Low-dose methotrexate in rheumatic diseases--efficacy, side effects, and risk factors for side effects. Semin Arthritis Rheum 1994; 5: 310–327.

38. Montaudie H, Sbidian E, Paul C, et al. Methotrexate in psoriasis: A systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity. J Eur Acad Dermatol Venereol 2011; 12–18.

39. Chladek J, Simkova M, Vaneckova J, et al. Assessment of methotrexate hepatotoxicity in psoriasis patients: A prospective evaluation of four serum fibrosis markers. J Eur Acad Dermatol Venereol 2013; 8: 1007–1014.

40. Lindsay K, Fraser AD, Layton A, et al. Liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose methotrexate therapy. Rheumatology (Oxford) 2009; 5: 569–572.

41. Gilani ST, Khan DA, Khan FA, et al. Adverse effects of low dose methotrexate in rheumatoid arthritis patients. J Coll Physicians Surg Pak 2012; 2: 101–104.

42. Attar SM. Adverse effects of low dose methotrexate in rheumatoid arthritis patients. Saudi Med J 2010; 8: 909–915.

43. Kinder AJ, Hassell AB, Brand J, et al. The treatment of inflammatory arthritis with methotrexate in clinical practice: Treatment duration and incidence of adverse drug reactions. Rheumatology (Oxford) 2005; 1: 61–66.

44. Rihacek I, Frana P, Soucek M, et al. The diurnal variability of blood pressure in patients with hypertension and rheumatoid arthritis. Vnitr Lek 2009; 2: 111–116.

45. Sterba J, Valik D, Bajciova V, et al. High-dose methotrexate and/or leucovorin rescue for the treatment of children with lymphoblastic malignancies: Do we really know why, when and how? Neoplasma 2005; 6: 456–463.

46. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist 2006; 6: 694–703.

47. Rysava R. Glomerular impairment associated with malignancies and chemotherapy induced nephrotoxicity. Postgrad Nefrol 2013; 4: 50–53.

48. Schwartz S, Borner K, Muller K, et al. Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist 2007; 11: 1299–1308.

49. Green JM. Glucarpidase to combat toxic levels of methotrexate in patients. Ther Clin Risk Manag 2012; 403–413.

50. Widemann BC, Balis FM, Shalabi A, et al. Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase g2. J Natl Cancer Inst 2004; 20: 1557–1559.

51. Oulego-Erroz I, Maneiro-Freire M, Bouzon-Alejandro M, et al. Anaphylactoid reaction to high-dose methotrexate and successful desensitization. Pediatr Blood Cancer 2010; 3: 557–559.

52. Umeda T, Takada N, Hodaka E, et al. [evaluation of severe side effects of high-dose methotrexate in osteosarcoma]. Gan To Kagaku Ryoho 1984; 2: 285–294.

53. Postovsky S, Elhasid R, Ben-Barak A, et al. Allergic reaction to high-dose methotrexate. Med Pediatr Oncol 2000; 2: 131–132.

54. Drachtman RA, Cole PD, Golden CB, et al. Dextromethorphan is effective in the treatment of subacute methotrexate. Pediatr Hematol Oncol 2002; 5: 319–327.

55. Valik D, Sterba J, Bajciova V, et al. Severe encephalopathy induced by the first but not the second course of high-dose methotrexate mirrored by plasma homocysteine elevations and preceded by extreme differences in pretreatment plasma folate. Oncology 2005; 3: 269–272.

56. Quinn CT, Griener JC, Bottiglieri T, et al. Elevation of homocysteine and excitatory amino acid neurotransmitters in the csf of children who receive methotrexate for the treatment of cancer. J Clin Oncol 1997; 8: 2800–2806.

57. Becker A, Vezmar S, Linnebank M, et al. Marked elevation in homocysteine and homocysteine sulfinic acid in the cerebrospinal fluid of lymphoma patients receiving intensive treatment with methotrexate. Int J Clin Pharmacol Ther 2007; 9: 504–515.

58. Takimoto CH. New antifolates: Pharmacology and clinical applications. Oncologist 1996; 1 & 2: 68–81.