Skip to main content
SpringerLink
Log in

Clinical Pharmacology and Resistance to Dihydrofolate Reductase Inhibitors

  • Chapter
Antifolate Drugs in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

It has been almost 50 years since aminopterin, the first drug capable of inducing complete remissions in children with acute lymphoblastic leukemia (ALL), was first tested (1). Methotrexate (MTX), also an antifolate inhibitor of dihydrofolate reductase (DHFR), soon after replaced aminopterin in the clinic and is used widely not only for the treatment of various forms of cancer, such as lymphoma, germ-cell tumors, breast cancer, and head and neck cancer but also for the treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis, and for the prevention of graft-vs-host disease (2). Al-though dramatic responses and even cures are observed in some malignancies with MTX treatment alone or in combination, in the majority of tumors, intrinsic resistance limits effectiveness. In malignancies that are initially sensitive to therapy, e.g., ALL, acquired resistance may develop, contributing to treatment failure and relapse (3).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  2. Gorlick R, Goker E, Trippett T, Waltham M, Banerjee D, Bertino JR. Intrinsic and acquired resistance to methotrexate in acute leukemia. N Engl J Med 1996;335:1041–1048.

    Article  PubMed  CAS  Google Scholar 

  3. Bertino JR. Ode to methotrexate. J Clin Oncol 1993;11:5–14.

    PubMed  CAS  Google Scholar 

  4. Goldman ID, Lichenstein WS, Oliveiro VT. Carrier-mediated transport of the folic acid analog methotrexate in the L1210 leukemia cell. J Biol Chem 1968;243:5007–5017.

    PubMed  CAS  Google Scholar 

  5. Sirotnak FM, Goutas LJ, Mines LS. Extent of requirement for folate transport by L1210 cells for growth and leukemogenesis in vivo. Cancer Res 1985;45:4732–4734.

    PubMed  CAS  Google Scholar 

  6. Antony AC. The biological chemistry of folate receptors. Blood 1992;79:2807–2820.

    PubMed  CAS  Google Scholar 

  7. Pizzorno G, Mini E, Coronnello M, McGuire JJ, Moroson BA, Cashmore AR, Dreyer RN, Lin JT, Mazzei T, Periti P, Bertino JR. Impaired polyglutamylation of methotrexate as a cause of resistance in CCRF-CEM cells after short-term, high-dose treatment with this drug. Cancer Res 1988;48:2149–2155.

    PubMed  CAS  Google Scholar 

  8. 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.

    PubMed  CAS  Google Scholar 

  9. Allegra CJ, Drake JC, Jolivet J, Chabner BA. Inhibition of phosphoribosylaminoimidazole carbox-amide transformylase by methotrexate and dihydrofolic acid polyglutamates. Proc Natl Acad Sci USA 1985;82:4881–4885.

    Article  PubMed  CAS  Google Scholar 

  10. Anderson RG, Kamen BA, Rothberg KG, Lacey SW. Potocytosis: sequestration and transport of small molecules by caveolae. Science 1992;255:410–411.

    Article  PubMed  CAS  Google Scholar 

  11. Lacey SW, Sanders JM, Rothberg KG, Anderson RG, Kamen BA. Complementary DNA for the fo-late binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol. J Clin Invest 1989;84:715–720.

    Article  PubMed  CAS  Google Scholar 

  12. Spinella MJ, Brigle KE, Sierra EE, Goldman ID. Distinguishing between folate receptor mediated transport and reduced folate carrier mediated transport in L1210 leukemia cells. J Biol Chem 1995;270:7842–7849.

    Article  PubMed  CAS  Google Scholar 

  13. Williams FMR, Murray RC, Underhill TM, Flintoff WF. Isolation of a hamster cDNA clone coding for a function involved in methotrexate uptake. J Biol Chem 1994;269:5810–5816.

    PubMed  CAS  Google Scholar 

  14. Dixon KH, Lampher BC, Chiu J, Kelley K, Cowan KH. A novel cDNA restores reduced folate carrier activity and methotrexate sensitivity to transport deficient cells. J Biol Chem 1994;269:17–20.

    PubMed  CAS  Google Scholar 

  15. Williams FMR, Flintoff WF. Isolation of a human cDNA that complements a mutant hamster cell de-fective in methotrexate uptake. J Biol Chem 1995;270:2987–2992.

    Article  PubMed  CAS  Google Scholar 

  16. Moscow JA, Gong M, He R, Sgagias MK, Dixon KH, Anzick SL, Meltzer PS, Cowan KH. Isolation of a gene encoding a human reduced folate carrier (RFC1) and analysis of its expression in transport-deficient methotrexate-resistant human breast cancer cells. Cancer Res 1995;55:3790–3795.

    PubMed  CAS  Google Scholar 

  17. Wong SC, Proefke SA, Bhushan A, Matherley LH. Isolation of human cDNAs that restore methotrex-ate sensitivity and reduced folate carrier activity in methotrexate transport-defective Chinese hamster ovary cells. J Biol Chem 1995;270:17,468–17,475.

    Google Scholar 

  18. Prasad PD, Ramamoorthy S, Leibach FH, Ganapathy V. Molecular cloning of the human placental fo-late transporter. Biochem Biophys Res Commun 1995;206:681–687.

    Article  PubMed  CAS  Google Scholar 

  19. Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski VR, Kamen BA. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res 1992;52:3396–3401.

    PubMed  CAS  Google Scholar 

  20. Campbell IG, Jones TA, Foulkes WD, Trowsdale J. Folate-binding protein is a marker for ovarian can-cer. Cancer Res 1991;51:5329–5338.

    PubMed  CAS  Google Scholar 

  21. Westerhof GR, Rijnbout S, Schomagel JH, Pinedo HM, Peters GJ, Jansen G. Functional activity of the reduced folate carrier in KB, MA104 and IGROV-1 cells expressing folate-binding protein. Cancer Res 1995;55:3795–3802.

    PubMed  CAS  Google Scholar 

  22. Mcguire JJ, Hsieh P, Coward JK, Bertino JR. Enzymatic synthesis of folylpolyglutamates. Character-ization of the reaction and its products. J Biol Chem 1980;255:5776–5788.

    PubMed  CAS  Google Scholar 

  23. Garrow TA, Admon A, Shane B. Expression cloning of a human cDNA encoding folylpoly (γ-gluta-mate) synthetase and determination of its primary structure. Proc Nati Acad Sci USA 1992;89:9151–9155.

    Article  CAS  Google Scholar 

  24. Chen L, Qi H, Korenberg J, Garrow TA, Choi YJ, Shane B. Purification and properties of human cy-tosolic folylpoly-–glutamate synthetase and organization, localization, and differential splicing of its gene. J Biol Chem 1996;271:13,077–13,087.

    Google Scholar 

  25. Roy K, Mitsugi K, Sirotnak FM. Organization and alternate splicing of the murine folylpolyglutamate synthetase gene. J Biol Chem 1996;271:23,820–23,827.

    Google Scholar 

  26. Roy K, Mitsugi K, Sirotnak FM. Additional organizational features of the murine folylpolyglutamate synthetase gene. J Biol Chem 1997;272:5587–5593.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  28. Galivan J, Johnson T, Rhee M, McGuire JJ, Priest D, Kesevan V. The role of folylpolyglutamate syn-thesis and gamma-glutamyl hydrolase in altering cellular foly- and antifolylpolyglutamates. Adv Enz Reg 1987;26:147–55.

    Article  CAS  Google Scholar 

  29. Wang Y, Dias JA, Nimec Z, Rotundo RM, O’Connor BM, Freisheim J, Galivan J. The properties and function of gamma-glutamyl hydrolase and poly-gamma-glutamate. Adv Enz Reg 1993;33:207–218.

    Article  CAS  Google Scholar 

  30. Samuels LL, Goutas LJ, Priest DG, Piper JR, Sirotnak FM. Hydrolytic cleavage of methotrexate gamma-polyglutamates by folylpolyglutamyl hydrolase derived from various tumors and normal tis-sues of the mouse. Cancer Res 1986;46:2230–2235.

    PubMed  CAS  Google Scholar 

  31. Waltham MC, Li WW, Gritsman H, Tong WP, Bertino JR. γ-Glutamyl hydrolase from human sar-coma HT-1080 cells: Characterization and inhibition by glutamine antagonists. Molec Pharmacol 1997;51:825–832.

    CAS  Google Scholar 

  32. Yao R, Nimec Z, Ryan TJ, Galivan J. Identification, cloning, and sequencing of a cDNA coding for rat y-glutamyl hydrolase. J Biol Chem 1996;271:8525–8528.

    Article  PubMed  CAS  Google Scholar 

  33. Yao R, Schneider E, Ryan TJ, Galivan J. Human gamma-glutamyl hydrolase: cloning and characteri-zation of the enzyme expressed in vitro. Proc Acad Sci USA 1996;93:10,134–10,138.

    Google Scholar 

  34. Bertino JR, Donohue DM, Simmons B, Gabrio BW, Silber R, Huennekens FM. The induction of di-hydrofolate reductase in leukocytes and erythrocytes of patients treated with methotrexate. J Clin In-vest 1963;42:466–475.

    Article  CAS  Google Scholar 

  35. Chu E, Koeller DM, Casey JL, Drake JC, Chabner BA, Elwood PC, Zinn S, Allegra CA. Autoregula-tion of human thymidylate synthase messenger RNA translation by thymidylate synthase. Proc Natl Acad Sci USA 1991;88:8977–8981.

    Article  PubMed  CAS  Google Scholar 

  36. Hillcoat BL, Swett V, Bertino JR. Increase of dihydrofolate reductase activity in cultured mammalian cells after exposure to methotrexate. Proc Natl Acad Sci USA 1967;58:1632–1637.

    Article  PubMed  CAS  Google Scholar 

  37. Ercikan-Abali E, Banerjee D, Waltham MC, Skacel N, Scotto KW, Bertino JR. Dihydrofolate reduc-tase protein inhibits its own translation by binding to dihydrofolate reductase mRNA sequences within the coding region. Biochemistry 1997;36:12317–12322.

    Article  PubMed  CAS  Google Scholar 

  38. Bertino JR, Kamen B, Romanini A. Folate antagonists, in Cancer Medicine, vol. 1 (Holland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR, eds.) Williams & Wilkins, Baltimore, 1997, pp. 907–921.

    Google Scholar 

  39. Chu E, Allegra CJ. Antifolates, in (Chabner BA, Longo DL, eds.) Cancer Chemotherapy and Bio-therapy. Lippincott-Raven, Philadelphia, 1996, pp. 109–14.

    Google Scholar 

  40. Chungi VS, Bourne DW, Dittert LW. Drug absorption VIII: kinetics of GI absorption of methotrex-ate. J Pharm Sci 1978;67:560–561.

    Article  PubMed  CAS  Google Scholar 

  41. Balis FM, Savitch JL, Bleyer WA. Pharmacokinetics of oral methotrexate in children. Cancer Res 1983;43:2342–2345.

    PubMed  CAS  Google Scholar 

  42. Steinberg SE, Campbell CL, Bleyer WA, Hillman RS. Enterohepatic circulation of methotrexate in rats in vivo. Cancer Res 1982;42:1279–1282.

    PubMed  CAS  Google Scholar 

  43. Steele WH, Lawrence JR, Stuart JF, McNeill CA. The protein binding of methotrexate by the serum of normal subjects. Eur J Clin Pharmacol 1979;15:363–366.

    Article  PubMed  CAS  Google Scholar 

  44. Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intra-venous ventricular and lumbar injections. N Eng J Med 1975;293:161–166.

    Article  CAS  Google Scholar 

  45. Wan SH, Huffman DH, Azarnoff DL, Stephens R, Hoogstraten B. Effect of route and administration and effusions on methotrexate pharmacokinetics. Cancer Res 1974;34:3487–3491.

    PubMed  CAS  Google Scholar 

  46. Calvert AH, Bondy PK, Harrap KR. Some observations on the human pharmacology of methotrexate. Cancer Treat Rep 1977;61:1647–1656.

    PubMed  CAS  Google Scholar 

  47. Kristensen LO, Weismann K, Hutters L. Renal function and the rate of disappearance of methotrexate from serum. Eur J Clin Pharmacol 1975;8:439–444.

    Article  PubMed  CAS  Google Scholar 

  48. Romolo JL, Goldberg NH, Hande KR, Rosenberg SA. Effect of hydration on plasma-methotrexate levels. Cancer Treat Rep 1977;61:1393–1396.

    PubMed  CAS  Google Scholar 

  49. Gewirtz DA, White JC, Randolph JK, Goldman ID. Transport, binding and polyglutamation of methotrexate in freshly isolated rat hepatocytes. Cancer Res 1980;40:573–578.

    PubMed  CAS  Google Scholar 

  50. Creaven PJ, Hansen HH, Alford DA, Allen LM. Methotrexate in liver and bile after intravenous dosage in man. Bri J Cancer 1973;28:589–591.

    Article  CAS  Google Scholar 

  51. Sonneveld P, Schultz FW, Nooter K, Hahlen K. Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in plasma and bone marrow of children receiving low-dose oral methotrexate. Cancer Chemother Pharmacol 1986;18:111–116.

    Article  PubMed  CAS  Google Scholar 

  52. Stewart AI, Margison JM, Wilkinson PM, Lucas SB. The pharmacokinetics of 7-hydroxymethotrex-ate following medium dose methotrexate therapy. Cancer Chemother Pharmacol 1985;14:165–167.

    Article  PubMed  CAS  Google Scholar 

  53. Jacobs SA, Stoller RG, Chabner BA, Johns DG. 7-Hydroxymethotrexate as a urinary metabolite in hu-man subjects and rhesus monkeys receiving high dose methotrexate. J Clin Invest 1976;57:534–538.

    Article  PubMed  CAS  Google Scholar 

  54. Valerino DM, Johns DG, Zaharko DS, Oliverio VT. Studies of the metabolism of methotrexate by in-testinal flora. I. Identification and study of biological properties of the metabolite 4-amino-4-deoxy-N 10-methylpteroic acid. Biochem Pharmacol 1972;21:821–831.

    Article  PubMed  CAS  Google Scholar 

  55. Daly H, Boyle J, Roberts C, Scott G. Interaction between methotrexate and non-steroidal anti-inflam-matory drugs. Lancet 1986;1:557.

    Article  PubMed  CAS  Google Scholar 

  56. Singh RR, Malaviya AN, Pandey JN, Guleria JS. Fatal interaction between methotrexate and naproxen. Lancet 1986;1:1390.

    Article  PubMed  CAS  Google Scholar 

  57. Maricic M, Davis M, Gall EP. Megaloblastic pancytopenia in a patient receiving concurrent methotrexate and trimethoprim-sulfamethoxazole treatment. Arthritis Rheum 1986;29:133–135.

    Article  PubMed  CAS  Google Scholar 

  58. Pinedo HM, Zaharko DS, Bull JM, Chabner BA. The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides. Cancer Res 1976;36:4418–4424.

    PubMed  CAS  Google Scholar 

  59. Howell SB, Ensminger WD, Krishan A, Frei E. Thymidine rescue of high-dose methotrexate in hu-mans. Cancer Res 1978;38:325–330.

    PubMed  CAS  Google Scholar 

  60. Widemann BC, Balis FM, Murphy RF, Sorensen JM, Montello MJ, O’Brien M, Adamson PC. Car-boxypeptidase-G2, thymidine and leucovorin rescue in cancer patients with methotrexate-induced re-nal dysfunction. J Clin Oncol 1997;15:2125–2134.

    PubMed  CAS  Google Scholar 

  61. Weber BL, Tanyer G, Poplack DG, Reaman GH, Feusner JH, Miser JS, Bleyer WA. Transient acute hepatotoxicity of high dose-methotrexate therapy during childhood. Natl Cancer Inst Monogr 1987;5:207–212.

    Google Scholar 

  62. Jaffe N, Takue Y, Anzai T, Robertson R. Transient neurologic disturbances induced by high-dose methotrexate treatment. Cancer 1985;56:1356–1360.

    Article  PubMed  CAS  Google Scholar 

  63. Clarysse AM, Cathey WJ, Cartwright GE, Wintrobe MM. Pulmonary disease complicating intermit-tent therapy with methotrexate. JAMA 1969;209:1861–1868.

    Article  PubMed  CAS  Google Scholar 

  64. Sostman HD, Matthay RA, Putman CE, Smith GJ. Methotrexate-induced pneumonitis. Medicine 1976;55:371–378.

    Article  PubMed  CAS  Google Scholar 

  65. Doyle LA, Berg C, Bottino G, Chabner B. Erythema and desquamation after high-dose methotrexate. Ann Int Med 1983;98:611–612.

    PubMed  CAS  Google Scholar 

  66. Hausknecht RU. Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 1995;333:537–540.

    Article  PubMed  CAS  Google Scholar 

  67. DeAngelis LM, Tong WP, Lin S, Fleisher M, Bertino JR. Carboxypeptidase G2 rescue after high-dose methotrexate. J Clin Oncol 1996;14:2145–2149.

    PubMed  CAS  Google Scholar 

  68. Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA. The pharmacology and clinical use of methotrexate. N Engl J Med 1983;309:1094–1104.

    Article  PubMed  CAS  Google Scholar 

  69. Schweitzer BI, Dicker AP, Bertino JR. Dihydrofolate reductase as a therapeutic target. FASEB J 1990;4:2441–2452.

    PubMed  CAS  Google Scholar 

  70. Lin JT, Tong WP, Trippett TM, Niedzwiecki D, Tao Y, Tan C, Steinherz P, Schweitzer BI, Bertino JR. Basis for natural resistance to methotrexate in human acute non-lymphocytic leukemia. Leukemia Res 1991;15:1191–1196.

    Article  CAS  Google Scholar 

  71. Goker E, Lin JT, Trippett T, Elisseyeff Y, Tong W, Niedzwiecki D, Tan C, Steinherz P, Schweitzer BI, Bertino JR. Decreased polyglutamylation of methotrexate in acute lymphoblastic leukemia blasts in adults compared to children with this disease. Leukemia 1993;7:1000–1004.

    PubMed  CAS  Google Scholar 

  72. Goker E, Kheradpour A, Waltham M, Banerjee D, Tong WP, Elisseyeff Y, Bertino JR. Acute mono-cytic leukemia: a myeloid subset that may be sensitive to methotrexate. Leukemia 1995;9:274–276.

    PubMed  CAS  Google Scholar 

  73. Hryniuk WM, Bertino JR. Treatment of leukemia with large doses of methotrexate and folinic acid: clinical-biochemical correlates. J Clin Invest 1969;48:2140–2155.

    Article  PubMed  CAS  Google Scholar 

  74. Rodenhuis S, Mcguire JJ, Narayanan R, Bertino JR. Development of an assay system for the detection and classification of methotrexate resistance in fresh human leukemia cells. Cancer Res 1986;46:6513–6519.

    PubMed  CAS  Google Scholar 

  75. Li WW, Lin JT, Tong WP, Trippett TM, Brennan MF, Bertino JR. Mechanisms of natural resistance to antifolates in human soft tissue sarcomas. Cancer Res 1992;52:1434–1438.

    PubMed  CAS  Google Scholar 

  76. Barakat RR, Li WW, Lovelace C, Bertino JR. Intrinsic resistance of cervical cell carcinoma cell lines to methotrexate (MTX) as a result of decreased accumulation of intracellular MTX polyglutamates. Gynecol Oncol 1993;93:2255–2262.

    Google Scholar 

  77. Pizzorno G, Chang YM, McGuire JJ, Bertino JR. Inherent resistance of human squamous carcinoma cell lines to methotrexate as a result of decreased polyglutamylation of this drug. Cancer Res 1989;49:5275–5280.

    PubMed  CAS  Google Scholar 

  78. Barredo JC, Synold TW, Laver J, Relling MV, Pui CH, Priest DG, Evans WE. Differences in consti-tutive and post-methotrexate folypolyglutamate synthetase activity in B-lineage and T-lineage leukemia. Blood 1994;84:564–569.

    PubMed  CAS  Google Scholar 

  79. Synold TW, Relling MV, Boyett JM, Rivera GK, Sandlund JT, Mahmoud H, Crist WM, Pui CH, Evans WE. Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 1994;94:1996–2001.

    Article  PubMed  CAS  Google Scholar 

  80. Whitehead VM, Rosenblatt DS, Vuchich MJ, Shuster JJ, Witte A, Beaulieu D. Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lym-phoblastic leukemia: a pilot prognostic factor analysis. Blood 1990;76:44–49.

    PubMed  CAS  Google Scholar 

  81. Argiris A, Longo GSA, Gorlick R, Tong W, Steinherz P, Bertino JR. Increased methotrexate polyg-lutamylation in acute megakaryocytic leukemia (M&) compare to other subtypes of acute myelocytic leukemia. Leukemia 1997;11:886–889.

    Article  PubMed  CAS  Google Scholar 

  82. Galpin AJ, Schuetz JD, Masson E, Yanishevski Y, Synold TW, Barredo JC, Pui CH, Relling MV, Evans WE. Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytotoxicity. Molec Pharmacol 1997;52:155–163.

    CAS  Google Scholar 

  83. Longo GSA, Gorlick R, Tong WP, Lin S, Steinherz P, Bertino JR. γ-Glutamyl hydrolase and foly-polyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias. Onc Res 1997;9:259–263.

    CAS  Google Scholar 

  84. Lenz HJ, Danenberg K, Schnieders B, Goker E, Peters GJ, Garrow T, Shane B, Bertino JR, Danen-berg PV. Quantitative analysis of folylpolyglutamate synthetase gene expression in tumor tissues by the polymerase chain reaction: marked variation of expression among leukemia patients. Oncol Res 1994;6:329–335.

    PubMed  CAS  Google Scholar 

  85. Li WW, Lin JT, Scweitzer BI, Tong WP, Niedzwiecki D, Bertino JR. Intrinsic resistance to methotrex-ate in human soft tissue sarcoma cell lines. Cancer Res 1992;52:3908–3913.

    PubMed  CAS  Google Scholar 

  86. Trippett T, Schlemmer S, Elisseyeff Y, Goker E, Wachter M, Steinherz P, Tan C, Berman E, Wright JE, Rosowsky A. Defective transport as a mechanism of acquired resistance to methotrexate in patients with acute leukemia. Blood 1992;80:1158–1162.

    PubMed  CAS  Google Scholar 

  87. Gorlick R, Goker E, Trippett T, Steinherz P, Elisseyeff Y, Mazumdar M, Flintoff WF, Bertino JR. De-fective transport is a common mechanism of acquired methotrexate resistance in acute lymphocytic leukemia and is associated with decreased reduced folate carrier expression. Blood 1997;89: 1013–1018.

    PubMed  CAS  Google Scholar 

  88. Brigle KE, Spinella MJ, Sierra EE, Goldman ID. Characterization of a mutation in the reduced folate carrier in a transport defective L1210 murine leukemia cell line. J Biol Chem 1995;270:22,974–22,979.

    Google Scholar 

  89. Gong M, Yess J, Connolly T, Ivy SP, Ohnuma T, Cowan KH, Moscow JA. Molecular mechanism of antifolate transport-deficiency in a methotrexate-resistant MOLT-3 human leukemia cell line. Blood 1997;89:2494–2499.

    PubMed  CAS  Google Scholar 

  90. Schimke RT. Gene amplification in cultured cells. J Biol Chem 1988;263:5989–5992.

    PubMed  CAS  Google Scholar 

  91. Srimatkandada S, Medina WD, Casnmore AR, Whyte W, Engel D, Moroson BA, Franco CT, Dube SK, Bertino JR. Amplification and organization of dihydrofolate reductase genes in a human leukemia cell line, K-562, resistant to methotrexate. Biochemistry 1983;22:5774–5781.

    Google Scholar 

  92. Stark GR, Debatisse M, Guilotto E, Wahl GM. Recent progress in understanding mechanisms of mam-malian DNA amplification. Cell 1989;57:901–908.

    Article  PubMed  CAS  Google Scholar 

  93. Goker E, Waltham M, Kheradpour A, Trippett T, Mazumdar M, Elisseyeff Y, Schnieders B, Steinherz P, Tan C, Berman E, Bertino JR. Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphocytic leukemia and is correlated with p53 gene mutations. Blood 1995;86:677–684.

    PubMed  CAS  Google Scholar 

  94. Matherly LH, Taub JW, Wong SC, Simpson PM, Ekizian R, Buck S, Williamson M, Amylon M, Pullen J, Camitta B, Ravindranath Y. Increased frequency of expression of elevated dihydrofolate re-ductase in T-cell versus B-precursor acute lymphoblastic leukemia in children. Blood 1997;90:578–589.

    PubMed  CAS  Google Scholar 

  95. Haber DA, Beverly SM, Kiely ML, Schimke RT. Properties of an altered dihydrofolate reductase en-coded by amplified genes in cultured mouse fibroblasts. J Biol Chem 1981;256:9501–9510.

    PubMed  CAS  Google Scholar 

  96. Srimatkandada S, Schweitzer BI, Moroson BA, Dube S, Bertino JR. Amplification of a polymorphic dihydrofolate reductase gene expressing an enzyme with a decreased binding to Methotrexate in a hu-man colon carcinoma cell line, HCT-8R4, resistant to this drug. J Biol Chem 1989;264:3524–3528.

    PubMed  CAS  Google Scholar 

  97. Melera PW, Davide JP, Hession CA, Scotto KW. Phenotypic expression in Escherichia coli and nu-cleotide sequence of two Chinese hamster lung cDNAs encoding different dihydrofolate reductases. Mol Cell Biol 1984;4:38–48.

    PubMed  CAS  Google Scholar 

  98. Dicker AP, Volkenandt M, Schweitzer BI, Banerjee D, Bertino JR. Identification and characterization of a mutation in the dihydrofolate reductase gene from methotrexate-resistant Chinese hamster ovary cell line Pro-3 Methotrexate RIII. J Biol Chem 1990;265:8317–8321.

    PubMed  CAS  Google Scholar 

  99. Spencer HT, Sorrentino BP, Pui CH, Chunduru SK, Sleep SEH, Blakley RL. Mutations in the gene for human dihydrofolate reductase: an unlikely cause of clinical relapse in pediatric leukemia patients af-ter therapy with methotrexate. Leukemia 1996;10:439–446.

    PubMed  CAS  Google Scholar 

  100. Hyde JE. The dihydrofolate reductase-thymidylate synthetase gene in the drug resistance of malaria parasites. Pharmacol Therapeutics 1990;48:45–59.

    Article  Google Scholar 

  101. Nevins JR. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science 1992;258:424–429.

    Article  PubMed  CAS  Google Scholar 

  102. Wells JM, Illenye S, Magae J, Wu, CL, Heintz NH. Accumulation of E2F-4-DP-1 DNA binding com-plexes correlates with induction of dhfr gene expression during the G1 to S phase transition. J Biol Chem 1997;272:4483–4492.

    Article  PubMed  CAS  Google Scholar 

  103. Li WW, Fan J, Hochhauser D, Banerjee D, Zielenski Z, Almasan A, Yin Y, Kelly R, Wahl GM, Bertino JR. Absence of functional retinoblastoma protein mediates increased resistance to an-timetabolites in human sarcoma cell lines. Proc Natl Acad Sci USA 1995;92:10,436–10,440.

    Google Scholar 

  104. Hochhauser D, Schnieders B, Ercikan-Abali E, Gorlick R, Muise-Helmericks R, Li WW, Fan J, Baner-jee D, Bertino JR. Effect of cyclin D 1 overexpression on drug sensitivity in a human fibrosarcoma cell line. J Natl Cancer Inst 1996;88:1269–1275.

    Article  PubMed  CAS  Google Scholar 

  105. Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 1992;70:923–935.

    Article  PubMed  CAS  Google Scholar 

  106. Yin Y, Tainsky MA, Bischoff FZ, Strong LC, Wahl GM. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 1992;70:937–948.

    Article  PubMed  CAS  Google Scholar 

  107. Hecker S, Sauerbrey A, Volm M. p53 expression and poor prognosis in childhood acute lymphoblas-tic leukemia. Anticancer Res 1994;14:2759–2761.

    PubMed  CAS  Google Scholar 

  108. Goldin A, Venditi JM, Humphreys SR, Dennis D, Mantel N, Greenhouse SW. A quantitative com-parison of the antileukemic effectiveness of two folic acid antagonists in mice. J Natl Cancer Inst 1955;15:1657–1664.

    PubMed  CAS  Google Scholar 

  109. Smith A, Hum M, Winick NJ, Kamen BA. A case for the use of aminopterin in treatment of patients with leukemia based on metabolic studies of blasts in vitro. Clin Cancer Res 1996;2:69–73.

    PubMed  CAS  Google Scholar 

  110. Glode LM, Pitman SW, Ensminger WD, Rosowsky A, Papathanasopoulos N, Frei E. A phase 1 study of high doses of aminopterin with leucovorin rescue in patients with advanced metastatic tumors. Can-cer Res 1979;39:3707–3714.

    CAS  Google Scholar 

  111. Kamen BA, Eibl B, Cashmore A, Bertino JR. Uptake and efficacy of trimetrexate (TMQ, 2,2-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline), a non-classical antifolate in methotrex-ate-resistant leukemia cells in vitro. Biochem Pharmacol 1984;33:1697–1699.

    Article  PubMed  CAS  Google Scholar 

  112. Allegra CJ, Chabner BA, Tuazon CU, Ogata-Arakaki D, Baird B, Drake JC, Simmons JT, Lack EE, Shelhamer JH, Balis F. Trimetrexate for the treatment of pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med 1987;317:978–985.

    Google Scholar 

  113. Takimoto CH, Allegra CJ. New antifolates in clinical development. Oncol 1995;9:649–656.

    CAS  Google Scholar 

  114. Seitz DE. Trimetrexate: A critical appraisal of the phase II clinical trial experience: evidence of drug discovery-clinical development disjunction. Cancer Invest 1994;12:657–661.

    Article  PubMed  CAS  Google Scholar 

  115. Pappo AS, Vats T, Williams TE, Bernstein M, Kamen BA. Phase I trial of trimetrexate in pediatric solid tumors: a Pediatric Oncology Group study. Med Ped Oncol 1993;21:280–282.

    Article  CAS  Google Scholar 

  116. Pappo A, Dubowy R, Ravindranath Y, Alvarado C, Rao S, Whitehead VM, Vega R, Kamen B, Vietti T. Phase II trial of trimetrexate in the treatment of recurrent childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Natl Cancer Inst 1990;82:1641–1642.

    Article  PubMed  CAS  Google Scholar 

  117. Kheradpour A, Berman E, Goker E, Lin JT, Tong WP, Bertino JR. A phase II study of continuous in-fusion of trimetrexate in patients with refractory leukemia. Cancer Invest 1995;13:36-–40.

    Google Scholar 

  118. Romanini A, Li WW, Colofiore JR, Bertino JR. Leucovorin enhances cytotoxicity of trimetrexate/flu-orouracil, but not methotrexate/fluorouracil in CCRF-CEM cells. J Natl Cancer Inst 1992;84: 1033–1038.

    Article  PubMed  CAS  Google Scholar 

  119. Conti JA, Kemeny N, Seiter K, Goker E, Tong W, Andre M, Ragusa K, Bertino JR. Trial of sequen-tial trimetrexate, fluorouracil and high-dose leucovorin in previously treated patients with gastroin-testinal carcinoma. J Clin Oncol 1994;12:695–700.

    PubMed  CAS  Google Scholar 

  120. Blanke CD, Kasimis B, Schein P, Capizzi R, Kurman M. Phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer. J Clin Oncol 1997;15:915–920.

    PubMed  CAS  Google Scholar 

  121. Sirotnak FM, Schmid FA, Samuels LL, Degraw JI. 10-Ethyl-l0-deaza-aminopterin: structural design and biochemical, pharmacological, and antitumor properties. Natl Cancer Inst Monographs 1987;5:127–131.

    Google Scholar 

  122. Grant SC, Kris MG, Young CW, Sirotnak FM. Edatrexate: an antifolate with antitumor activity: a re-view. Cancer Invest 1993;11:36–45.

    Article  PubMed  CAS  Google Scholar 

  123. Casper ES, Christman KL, Schwartz GK, Johnson B, Brennan MF, Bertino JR. Edatrexate in patients with soft tissue sarcoma. Activity in malignant fibrous histiocytoma. Cancer 1993;72:766–770.

    Article  PubMed  CAS  Google Scholar 

  124. Mauritz R, Bekkenk M, Pieters R, Veerman AJP, Peters GJ, Jansen G. Resistance to methotrexate and sensitivity for novel antifolates in different types of childhood leukemia. Blood 1994;84:45a.

    Google Scholar 

  125. Jackson RC, Fry DW, Boritzki TJ, Besserer JA, Leopold WR, Sloan BJ, Elslager EF. Biochemical pharmacology of the lipophilic antifolate, trimetrexate. Adv Enz Reg 1984;22:187–206.

    Article  CAS  Google Scholar 

  126. Lacerda JF, Goker E, Kheradpour A, Dennig D, Elisseyeff Y, Jagiello C, O’Reilly RJ, Bertino JR. Se-lective treatment of SCID mice bearing methotrexate-transport-resistant human acute lymphoblastic leukemia tumors with trimetrexate and leucovorin protection. Blood 1995;85:2675–2679.

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. Richard Gorlick
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph R. Bertino
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. The Cancer Research Campaign Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK

    Ann L. Jackman

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Science+Business Media New York

About this chapter

Cite this chapter

Gorlick, R., Bertino, J.R. (1999). Clinical Pharmacology and Resistance to Dihydrofolate Reductase Inhibitors. In: Jackman, A.L. (eds) Antifolate Drugs in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-725-3_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-725-3_3

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4757-4521-4

  • Online ISBN: 978-1-59259-725-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation