Folate During Antifolate Chemotherapy: What We Know... and Do Not Know

Abstract

The nutrient folate is essential for normal cell growth and development. Enzymes that require folate as a cofactor have been common targets for chemotherapeutic agents. Limited clinical guidance is available regarding optimal levels of dietary or supplemental folate intake during antifolate chemotherapy to meet the goals of minimizing treatment-related toxicity yet preserving treatment effectiveness. Patients with higher folate intake may experience less treatment-related toxicities; however, the concern is that folate may interfere with the effectiveness of the antifolate treatment and possibly support tumor growth. This article will review folate and antifolate metabolism and review the current body of knowledge regarding the interactions between folates and antifolates. Future research in this area should include evaluation of pretreatment folate status and dietary and supplemental folate intake before, during, and after treatment.

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References

Wills L, Mehta MM. Studies in “pernicious anemia” of pregnancy, I: preliminary report. Indian J Med Res. 1930 ;17:777– 792.

Wills L. Treatment of “pernicious anemia of pregnancy” and “tropical anemia” with special reference to yeast extract as curative agent. BMJ. 1931 ;1:1059– 1064.

Mitchell HK, Snell EE, Williams RJ. The concentration of“ folic acid” [letter]. J Am Chem Soc. 1941 ;63:2284 .

Bertino JR. Karnofsky memorial lecture: ode to methotrexate. J Clin Oncol. 1993 ;11:5– 14.

Heinle RW, Welch AD. Experiments with pteroylglutamic acid and pteroglutamic acid deficiency in human leukemia. J Clin Invest. 1948;27:539 .

Seeger DR, Smith JM, Hultquist ME. Antagonist for pteroylglutamic acid. J Am Chem Soc. 1947 ;69:2567 .

Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA. Temporary remissions in acute leukemia in children produced by folic acid antogonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med. 1948;238:787– 793.

Institute of Medicine. Folate. In: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Niacin, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: Institute of Medicine, Subcommittee of Folate, Other B Vitamins, and Choline;1998 : 196–305.

Cosulich DB, Hultquist ME, Seeger DR. The chemistry of certain pteroylglutamic acid antagonists. Trans N Y Acad Sci. 1948 ;10:82– 83.

10.

Chu E, Allegra CJ. Antifolates. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy, 2nd ed. Philadelphia, PA: Lippincott-Raven Publishers; 1996:109– 148.

11.

Allegra CJ, Chabner BA, Drake JC, Lutz R, Rodbard D, Jolivet J. Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. J Biol Chem. 1985 ;260:9720– 9726.

12.

Vinnicombe HG, Derrick JP. Dihydropteroate synthase: an old drug target revisited. Biochem Soc Trans. 1999 ;27:53– 58.

13.

Kisliuk RL. Folate biochemistry in relation to antifolate selectivity. In: Jackman AL, ed. Anticancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Totowa, NJ: Humana Press Inc;1999 : 13–36.

14.

Calvert H. An overview of folate metabolism: features relevant to the action and toxicities of antifolate anticancer agents. Semin Oncol. 1999;26:3– 10.

15.

Barredo JC, Synold TW, Laver J, et al. Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia. Blood. 1994 ;84:564– 569.

16.

Longo GS, Gorlick R, Tong WP, Ercikan E, Bertino JR. Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells. Blood. 1997 ;90:1241– 1245.

17.

Gates SB, Worzalla JF, Shih C, Grindey GB, Mendelsohn LG. Dietary folate and folylpolyglutamate synthetase activity in normal and neoplastic murine tissues and human tumor xenografts. Biochem Pharmacol. 1996;52:1477– 1479.

18.

Schilsky RL, Bailey BD, Chabner BA. Methotrexate polyglutamate synthesis by cultured human breast cancer cells. Proc Natl Acad Sci U S A. 1980;77:2919– 2922.

19.

McGuire JJ. Anticancer antifolates: current status and future directions. Curr Pharm Des. 2003 ;9:2593– 2613.

20.

Calvert H. Folate status and the safety profile of antifolates. Semin Oncol. 2002 ;29:3– 7.

21.

Sierra EE, Goldman ID. Recent advances in the understanding of the mechanism of membrane transport of folates and antifolates. Semin Oncol. 1999;26:11– 23.

22.

Zhao R, Gao F, Goldman ID. Marked suppression of the activity of some, but not all, antifolate compounds by augmentation of folate cofactor pools within tumor cells. Biochem Pharmacol. 2001 ;61:857– 865.

23.

Roberts JD, Poplin EA, Tombes MB, et al. Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation. Cancer Chemother Pharmacol. 2000 ;45:103– 110.

24.

Mead JAR, Venditti JM, Schrecker AW, Goldin A, Keresztesy JC. The effect of reduced derivatives of folic acid on toxicity and antileukemic effect of methotrexate in mice. Biochemical Pharmacology. 1963;12:371– 383.

25.

Parchure M, Ambaye RY, Gokhale SV. Combination of anticancer agents with folic acid in the treatment of murine leukaemia P388. Chemotherapy. 1984 ;30:119– 124.

26.

Schroder H, Clausen N, Ostergard E, Pressler T. Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1986 ;3:241– 247.

27.

Sullivan RD, Miller E, Sikes MP. Antimetabolite-metabolite combination cancer chemotherapy: effects of intraarterial methotrexate-intramuscular Citrovorum factor therapy in human cancer. Cancer. 1959;12:1248– 1262.

28.

Kamen BA. High-dose methotrexate and asparaginase for the treatment of children with acute lymphoblastic leukemia: why and how? J Pediatr Hematol Oncol. 2004 ;26:333– 335.

29.

Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA. Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med. 1977 ;297:630– 634.

30.

Hum MC, Kamen BA. Folate, antifolates, and folate analogs in pediatric oncology. Invest New Drugs. 1996 ;14:101– 111.

31.

Cohen IJ. Defining the appropriate dosage of folinic acid after high-dose methotrexate for childhood acute lymphatic leukemia that will prevent neurotoxicity without rescuing malignant cells in the central nervous system. J Pediatr Hematol Oncol. 2004 ;26:156– 163.

32.

Borsi JD, Wesenberg F, Stokland T, Moe PJ. How much is too much? Folinic acid rescue dose in children with acute lymphoblastic leukaemia. Eur J Cancer. 1991 ;27:1006– 1009.

33.

Browman GP, Goodyear MD, Levine MN, Russell R, Archibald SD, Young JE. Modulation of the antitumor effect of methotrexate by low-dose leucovorin in squamous cell head and neck cancer: a randomized placebo-controlled clinical trial. J Clin Oncol. 1990;8 : 203–208.

34.

Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis: a double-blind, placebo-controlled trial. Ann Intern Med. 1994 ;121:833– 841.

35.

van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2001;44:1515– 1524.

36.

Ortiz Z, Shea B, Suarez Almazor M, Moher D, Wells G, Tugwell P. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2000:CD000951 .

37.

Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology (Oxford). 2004;43:267– 271.

38.

Endresen GK, Husby G. Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis: an update and proposals for guidelines. Scand J Rheumatol. 2001;30 : 129–134.

39.

Taylor EC, Kuhnt D, Shih C, et al. A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem. 1992;35:4450– 4454.

40.

Worzalla JF, Shih C, Schultz RM. Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514. Anticancer Res. 1998 ;18:3235– 3239.

41.

Niyikiza C, Baker SD, Seitz DE, et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther. 2002 ;1:545– 552.

42.

Bajetta E, Celio L, Buzzoni R, et al. Phase II study of pemetrexed disodium (Alimta) administered with oral folic acid in patients with advanced gastric cancer. Ann Oncol. 2003 ;14:1543– 1548.

43.

Scagliotti GV, Shin DM, Kindler HL, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol. 2003 ;21:1556– 1561.

44.

Adjei AA. Pemetrexed (Alimta): a novel multitargeted antifolate agent. Expert Rev Anticancer Ther. 2003 ;3:145– 156.

45.

Allegra CJ, Chabner BA, Tuazon CU, et al. Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1987 ;317:978– 985.

46.

MacDonald JR, Courtney CL, Pegg DG. Leucovorin protection against repeated daily dose toxicity of trimetrexate in rats. Fundam Appl Toxicol. 1993;21:244– 252.

47.

Hum M, Holcenberg JS, Tkaczewski I, Weaver JW, Wilson J, Kamen BA. High-dose trimetrexate and minimal-dose leucovorin: a case for selective protection? Clin Cancer Res. 1998 ;4:2981– 2984.

48.

Jolivet J, Jansen G, Peters GJ, Pinard MF, Schornagel JH. Leucovorin rescue of human cancer and bone marrow cells following edatrexate or methotrexate. Biochem Pharmacol. 1994 ;47:659– 665.

49.

Lee JS, Murphy WK, Shirinian MH, Pang A, Hong WK. Alleviation by leucovorin of the dose-limiting toxicity of edatrexate: potential for improved therapeutic efficacy. Cancer Chemother Pharmacol. 1991 ;28:199– 204.

50.

Kindler HL, Belani CP, Herndon JE 2nd, Vogelzang NJ, Suzuki Y, Green MR. Edatrexate (10-ethyl-deaza-aminopterin) (NSC #626715) with or without leucovorin rescue for malignant mesothelioma: sequential phase II trials by the cancer and leukemia group B. Cancer. 1999 ;86:1985– 1991.

51.

Mendelsohn LG, Gates SB, Habeck LL, et al. The role of dietary folate in modulation of folate receptor expression, folylpolyglutamate synthetase activity and the efficacy and toxicity of lometrexol. Adv Enzyme Regul. 1996 ;36:365– 381.

52.

Alati T, Worzalla JF, Shih C, et al. Augmentation of the therapeutic activity of lometrexol, (6-R)5,10-dideazatetrahydrofolate, by oral folic acid. Cancer Res. 1996 ;56:2331– 2335.

53.

Habeck LL, Chay SH, Pohland RC, Worzalla JF, Shih C, Mendelsohn LG. Whole-body disposition and polyglutamate distribution of the GAR formyltransferase inhibitors LY309887 and lometrexol in mice: effect of low-folate diet. Cancer Chemother Pharmacol. 1998 ;41:201– 209.

54.

Ray MS, Muggia FM, Leichman CG, et al. Phase I study of (6R)-5,10-dideazatetrahydrofolate: a folate antimetabolite inhibitory to de novo purine synthesis. J Natl Cancer Inst. 1993 ;85:1154– 1159.

55.

Wedge SR, Laohavinij S, Taylor GA, Boddy A, Calvert AH, Newell DR. Clinical pharmacokinetics of the antipurine antifolate (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolic acid (Lometrexol) administered with an oral folic acid supplement. Clin Cancer Res. 1995 ; 1:1479– 1486.

56.

Relling MV, Dervieux T. Pharmacogenetics and cancer therapy. Natl Rev Cancer. 2001 ;1:99– 108.

57.

Ulrich CM, Robien K, Sparks R. Pharmacogenetics of folate metabolism: a promising direction. Pharmacogenomics. 2002 ;3:299– 313.

58.

Krajinovic M, Moghrabi A. Pharmacogenetics of methotrexate. Pharmacogenomics. 2004 ;5:819– 834.

59.

Laverdiere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood. 2002 ;100:3832– 3834.

60.

Kaufman Y, Drori S, Cole PD, et al. Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia. Cancer. 2004 ; 100:773– 782.

61.

Yang R, Sowers R, Mazza B, et al. Sequence alterations in the reduced folate carrier are observed in osteosarcoma tumor samples. Clin Cancer Res. 2003 ;9:837– 844.

62.

Zhao R, Assaraf YG, Goldman ID. A reduced folate carrier mutation produces substrate-dependent alterations in carrier mobility in murine leukemia cells and methotrexate resistance with conservation of growth in 5-formyltetrahydrofolate. J Biol Chem. 1998 ;273:7873– 7879.

63.

Drori S, Jansen G, Mauritz R, Peters GJ, Assaraf YG. Clustering of mutations in the first transmembrane domain of the human reduced folate carrier in GW1843U89-resistant leukemia cells with impaired antifolate transport and augmented folate uptake. J Biol Chem. 2000 ;275:30855– 30863.

64.

Ding BC, Witt TL, Hukku B, Heng H, Zhang L, Matherly LH. Association of deletions and translocation of the reduced folate carrier gene with profound loss of gene expression in methotrexate-resistant K562 human erythroleukemia cells. Biochem Pharmacol. 2001 ;61:665– 675.

65.

Ulrich CM, Yasui Y, Storb R, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood. 2001;98:231– 234.

66.

Chiusolo P, Reddiconto G, Casorelli I, et al. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol. 2002 ;13:1915– 1918.

67.

Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A. Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J. 2004;41:66– 72.

68.

Kishi S, Griener J, Cheng C, et al. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol. 2003;21:3084– 3091.

69.

Robien K, Schubert MM, Bruemmer B, Lloid ME, Potter JD, Ulrich CM. Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia. J Clin Oncol. 2004;22:1268– 1275.

70.

Robien K, Ulrich CM, Bigler J, et al. Methylenetetrahydrofolate reductase genotype affects risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia. Clin Cancer Res. 2004;10:7592– 7598.

71.

Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci. 2001;22:195– 201.

72.

Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 ;10:111– 113.

73.

van der Put NM, Gabreels F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998 ;62:1044– 1051.

74.

Duthie SJ, Narayanan S, Blum S, Pirie L, Brand GM. Folate deficiency in vitro induces uracil misincorporation and DNA hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cells. Nutr Cancer. 2000 ;37:245– 251.

75.

Kim YI, Pogribny IP, Basnakian AG, et al. Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am J Clin Nutr. 1997 ;65:46– 52.

76.

Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol. 1999 ;6:359– 365.

77.

Yamada K, Chen Z, Rozen R, Matthews RG. Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci U S A. 2001 ; 98:14853– 14858.