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Br J Cancer. 1998; 78 (Suppl 3): 1–7.
PMCID: PMC2062805

New antimetabolites in cancer chemotherapy and their clinical impact.

Abstract

It is almost 50 years since antimetabolites were first found to have clinical antitumour activity, with Farber's discovery that aminopterin could cause remission in acute leukaemia. In the following 10 years, methotrexate, 6-mercaptopurine and 5-fluorouracil (5-FU) found their way into clinical practice. Subsequently, cytosine arabinoside was found to have activity in acute leukaemia, but, until recently, other significant developments have involved optimizing the efficacy of existing antimetabolites, including the use of leucovorin with methotrexate or 5-FU. Recently, new antimetabolites have become a fertile area for anti-cancer drug research. Gemcitabine (GEMZAR) has emerged as an important new agent in several tumour types, including pancreatic, non-small-cell lung, bladder, breast and ovarian cancers. Capecitabine is an intriguing new prodrug, offering tumour selectivity and prolonged tumour exposure to 5-FU. More potent thymidylate synthase inhibitors have also emerged; raltitrexed is now commercially available for the treatment of colorectal cancer. Others under development include LY231514, which has other sites of action, hence the acronym MTA (multi-targeted antifolate). A novel target is glycinamide ribonucleotide formyltransferase (GARFT) and LY309887 and AG2034 are undergoing clinical investigation as GARFT inhibitors. A critical element with LY309887 appears to be co-administration of folate. It seems entirely possible that several novel antimetabolites will establish themselves in clinical practice in future for the treatment of solid tumours.

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Selected References

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  • Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol. 1991 Mar;9(3):491–498. [PubMed]
  • Abratt RP, Bezwoda WR, Falkson G, Goedhals L, Hacking D, Rugg TA. Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study. J Clin Oncol. 1994 Aug;12(8):1535–1540. [PubMed]
  • Allegra CJ, Hoang K, Yeh GC, Drake JC, Baram J. Evidence for direct inhibition of de novo purine synthesis in human MCF-7 breast cells as a principal mode of metabolic inhibition by methotrexate. J Biol Chem. 1987 Oct 5;262(28):13520–13526. [PubMed]
  • Anderson H, Lund B, Bach F, Thatcher N, Walling J, Hansen HH. Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol. 1994 Sep;12(9):1821–1826. [PubMed]
  • Boritzki TJ, Barlett CA, Zhang C, Howland EF. AG2034: a novel inhibitor of glycinamide ribonucleotide formyltransferase. Invest New Drugs. 1996;14(3):295–303. [PubMed]
  • Burris HA, 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403–2413. [PubMed]
  • Cantwell BM, Macaulay V, Harris AL, Kaye SB, Smith IE, Milsted RA, Calvert AH. Phase II study of the antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717) in advanced breast cancer. Eur J Cancer Clin Oncol. 1988 Apr;24(4):733–736. [PubMed]
  • Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731–2736. [PubMed]
  • Feun LG, Savaraj N, Benedetto P, Hanlon J, Sridhar KS, Collier M, Richman S, Liao SH, Clendeninn NJ. Phase I trial of piritrexim capsules using prolonged, low-dose oral administration for the treatment of advanced malignancies. J Natl Cancer Inst. 1991 Jan 2;83(1):51–55. [PubMed]
  • 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 Oct 3;335(14):1041–1048. [PubMed]
  • Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med. 1983 Dec 30;75(6A):69–73. [PubMed]
  • Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2',2'-difluorodeoxycytidine on DNA synthesis. Cancer Res. 1991 Nov 15;51(22):6110–6117. [PubMed]
  • Jackman AL, Kimbell R, Brown M, Brunton L, Harrap KR, Wardleworth JM, Boyle FT. The antitumour activity of ZD9331, a non-polyglutamatable quinazoline thymidylate synthase inhibitor. Adv Exp Med Biol. 1994;370:185–188. [PubMed]
  • Johnston PG, Fisher ER, Rockette HE, Fisher B, Wolmark N, Drake JC, Chabner BA, Allegra CJ. The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol. 1994 Dec;12(12):2640–2647. [PubMed]
  • Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA. The pharmacology and clinical use of methotrexate. N Engl J Med. 1983 Nov 3;309(18):1094–1104. [PubMed]
  • Kay AC, Saven A, Carrera CJ, Carson DA, Thurston D, Beutler E, Piro LD. 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. J Clin Oncol. 1992 Mar;10(3):371–377. [PubMed]
  • Kaye SB. Gemcitabine: current status of phase I and II trials. J Clin Oncol. 1994 Aug;12(8):1527–1531. [PubMed]
  • Keating MJ, McCredie KB, Bodey GP, Smith TL, Gehan E, Freireich EJ. Improved prospects for long-term survival in adults with acute myelogenous leukemia. JAMA. 1982 Nov 19;248(19):2481–2486. [PubMed]
  • Laohavinij S, Wedge SR, Lind MJ, Bailey N, Humphreys A, Proctor M, Chapman F, Simmons D, Oakley A, Robson L, et al. A phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid. Invest New Drugs. 1996;14(3):325–335. [PubMed]
  • Leichman L, Lenz HJ, Leichman CG, Groshen S, Danenberg K, Baranda J, Spears CP, Boswell W, Silberman H, Ortega A, et al. Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-fluorouracil and weekly leucovorin in disseminated colorectal cancers: preliminary report from an ongoing trial. Eur J Cancer. 1995 Jul-Aug;31A(7-8):1306–1310. [PubMed]
  • Lenz HJ, Leichman CG, Danenberg KD, Danenberg PV, Groshen S, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, et al. Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol. 1996 Jan;14(1):176–182. [PubMed]
  • McDonald CJ. The uses of systemic chemotherapeutic agents in psoriasis. Pharmacol Ther. 1981;14(1):1–24. [PubMed]
  • Marshall JL, DeLap RJ. Clinical pharmacokinetics and pharmacology of trimetrexate. Clin Pharmacokinet. 1994 Mar;26(3):190–200. [PubMed]
  • Mendelsohn LG, Gates SB, Habeck LL, Shackelford KA, Worzalla J, Shih C, Grindey GB. 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. [PubMed]
  • Mendelsohn LG, Shih C, Schultz RM, Worzalla JF. Biochemistry and pharmacology of glycinamide ribonucleotide formyltransferase inhibitors: LY309887 and lometrexol. Invest New Drugs. 1996;14(3):287–294. [PubMed]
  • Miwa M, Ishikawa T, Eda H, Ryu M, Fujimoto K, Ninomiya Y, Umeda I, Yokose K, Ishitsuka H. Comparative studies on the antitumor and immunosuppressive effects of the new fluorouracil derivative N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and its parent drug 5'-deoxy-5-fluorouridine. Chem Pharm Bull (Tokyo) 1990 Apr;38(4):998–1003. [PubMed]
  • Moertel CG. Chemotherapy of gastrointestinal cancer. N Engl J Med. 1978 Nov 9;299(19):1049–1052. [PubMed]
  • Pestalozzi BC, Peterson HF, Gelber RD, Goldhirsch A, Gusterson BA, Trihia H, Lindtner J, Cortés-Funes H, Simmoncini E, Byrne MJ, et al. Prognostic importance of thymidylate synthase expression in early breast cancer. J Clin Oncol. 1997 May;15(5):1923–1931. [PubMed]
  • 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 Dec;36(12):4418–4424. [PubMed]
  • Pollera CF, Ceribelli A, Crecco M, Calabresi F. Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol. 1994 Feb;5(2):182–184. [PubMed]
  • Porter DJ, Chestnut WG, Merrill BM, Spector T. Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J Biol Chem. 1992 Mar 15;267(8):5236–5242. [PubMed]
  • Ray MS, Muggia FM, Leichman CG, Grunberg SM, Nelson RL, Dyke RW, Moran RG. Phase I study of (6R)-5,10-dideazatetrahydrofolate: a folate antimetabolite inhibitory to de novo purine synthesis. J Natl Cancer Inst. 1993 Jul 21;85(14):1154–1159. [PubMed]
  • Richel DJ, Colly LP, Lurvink E, Willemze R. Comparison of the antileukaemic activity of 5 aza-2-deoxycytidine and arabinofuranosyl-cytosine in rats with myelocytic leukaemia. Br J Cancer. 1988 Dec;58(6):730–733. [PMC free article] [PubMed]
  • Rinaldi DA, Burris HA, Dorr FA, Woodworth JR, Kuhn JG, Eckardt JR, Rodriguez G, Corso SW, Fields SM, Langley C, et al. Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol. 1995 Nov;13(11):2842–2850. [PubMed]
  • Sessa C, Zucchetti M, Ginier M, Willems Y, D'Incalci M, Cavalli F. Phase I study of the antifolate N10-propargyl-5,8-dideazafolic acid, CB 3717. Eur J Cancer Clin Oncol. 1988 Apr;24(4):769–775. [PubMed]
  • Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF, et al. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997 Mar 15;57(6):1116–1123. [PubMed]
  • Sirotnak FM, DeGraw JI, Moccio DM, Samuels LL, Goutas LJ. New folate analogs of the 10-deaza-aminopterin series. Basis for structural design and biochemical and pharmacologic properties. Cancer Chemother Pharmacol. 1984;12(1):18–25. [PubMed]
  • Takemura Y, Jackman AL. Folate-based thymidylate synthase inhibitors in cancer chemotherapy. Anticancer Drugs. 1997 Jan;8(1):3–16. [PubMed]
  • Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, Jannatipour M, Moran RG. 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 Nov 13;35(23):4450–4454. [PubMed]
  • Webber SE, Bleckman TM, Attard J, Deal JG, Kathardekar V, Welsh KM, Webber S, Janson CA, Matthews DA, Smith WW, et al. Design of thymidylate synthase inhibitors using protein crystal structures: the synthesis and biological evaluation of a novel class of 5-substituted quinazolinones. J Med Chem. 1993 Mar 19;36(6):733–746. [PubMed]
  • Webber S, Bartlett CA, Boritzki TJ, Hillard JA, Howland EF, Johnston AL, Kosa M, Margosiak SA, Morse CA, Shetty BV. AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies. Cancer Chemother Pharmacol. 1996;37(6):509–517. [PubMed]
  • Zalcberg JR, Cunningham D, Van Cutsem E, Francois E, Schornagel J, Adenis A, Green M, Iveson A, Azab M, Seymour I. ZD1694: A novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. Tomudex Colorectal Study Group. J Clin Oncol. 1996 Mar;14(3):716–721. [PubMed]

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