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Improving Fluorouracil Chemotherapy with Novel Orally Administered Fluoropyrimidines

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Abstract

During the 40 years since the initial synthesis of fluorouracil, there have been many attempts to improve fluoropyrimidine chemotherapy. These have included the utilisation of different schedules of fluorouracil administration, modulation of the metabolism of fluorouracil with other drugs to increase its therapeutic benefit, and the synthesis of prodrugs of fluorouracil that are potentially more effective and less toxic. Of particular interest at present is the clinical evaluation of several new fluoropyrimidine drugs that can be orally administered. These include capecitabine, tegafur/uracil (UFT®), eniluracil (GW-776C85; 5-ethynyluracil), S-1, and emitefur (BOF-A2). The pharmacological principles that have influenced the development of these new drugs are initially presented. This is followed by a review of our current knowledge of the clinical pharmacology of each of these new agents, focusing on antitumour activity and toxicity from studies conducted in the US. Studies of capecitabine, tegafur/uracil, and early studies with eniluracil indicate that these drugs have at least similar activity to protracted fluorouracil infusion but with additional quality-of-life and economic benefits.

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References

  1. Allegra C, Grem J. Pharmacology of cancer chemotherapy —antimetabolites. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer —principles and practice of oncology. Philadelphia: JB Lippincott, 1997: 432–51

    Google Scholar 

  2. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 1989; 16: 215–37

    Article  PubMed  CAS  Google Scholar 

  3. Daher GC, Harris BE, Diasio RB. Metabolism of pyrimidine analogues and their nucleosides. In: Powis G, editor. Anticancer drugs: antimetabolite metabolism and natural anticancer agents. Oxford: Pergamon Press, 1994: 55–94

    Google Scholar 

  4. Lu Z-H, Zhang R, Diasio RB. Purification and characterization of dihydropyrimidine dehydrogenase from human liver. J Biol Chem 1992; 267: 17102–9

    PubMed  CAS  Google Scholar 

  5. Heggie GD, Sommadossi JP, Cross DS, et al. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 1987; 47: 2203–6

    PubMed  CAS  Google Scholar 

  6. Spector T, Porter DJ, Nelson ST, et al. 5-Ethynyluracil (776C85), a modulator of the therapeutic activity of 5-fluorouracil. Drugs Future 1994; 19: 566–71

    Google Scholar 

  7. Lokich JJ, Ahlgren JD, Gullo JJ, et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol 1989; 7: 425–33

    PubMed  CAS  Google Scholar 

  8. Grem JL. 5-Fluoropyrimidines. In: Chabner BA, Longo DL, editors. Cancer chemotherapy and biotherapy, principles and practice. Philadelphia: JB Lippincott, 1996: 149–212

    Google Scholar 

  9. Wright JE, Dreyfuss A, El-Magharbel I, et al. Selective expansion of 5,10-methylenetetrahydrofolate pools and modulation of 5-fluorouracil antitumor activity by leucovorin in vivo. Cancer Res 1989; 49: 2592–6

    PubMed  CAS  Google Scholar 

  10. Ishitsuka H, Miwa M, Ishikawa T, et al. Capecitabine, an orally available fluoropyrimidine with tumor selective activity. Proc Am Assoc Cancer Res 1995; 36: 407A

    Google Scholar 

  11. Bajetta E, Carnaghi C, Somma L, et al. A pilot safety study of capecitabine, a new oral fluoropyrimidine, in patients with advanced neoplastic disease. Tumori 1996; 82: 450–2

    PubMed  CAS  Google Scholar 

  12. Ishikawa T, Sekiguchi F, Fukase Y, et al. Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 1998; 58: 685–90

    PubMed  CAS  Google Scholar 

  13. Cao S, Lu K, Ishitsuka H, et al. Antitumor efficacy of capecitabine against fluorouracil-sensitive and -resistant tumors. Proc Am Soc Clin Oncol 1997; 16: 226A

    Google Scholar 

  14. Meropol NG, Budman DR, Creaven PJ, et al. A phase I study of continuous twice daily treatment with capecitabine in patients with advanced and/or metastatic solid tumors. Ann Oncol 1996; 7 Suppl. 1: 87

    Google Scholar 

  15. Hughes M, Planting A, Twelves C, et al. A phase I study of intermittent twice daily oral therapy with capecitabine in patients with advanced and/or metastatic solid tumors. Ann Oncol 1996; 7 Suppl. 1: 87

    Google Scholar 

  16. O’Shaughnessy J, Moiseyenko D, Bell JM, et al. A randomized phase II study of Xeloda™ (capecitabine) vs CMF as first line chemotherapy of breast cancer in women aged ≥55 years. Proc Am Soc Clin Oncol 1998; 17: 103A

    Google Scholar 

  17. Gieschke R, Steimer J-L, Reigner BG. Relationships between metrics of exposure to Xeloda™ and occurrence of adverse effects. Proc Am Soc Clin Oncol 1998; 17: 223A

    Google Scholar 

  18. Fujii S, Kitano S, Ikenaka K, et al. Effect of coadministration of uracil or cytosine on the antitumor activity of clinical doses of l-(2-tetrahydrofuryl)-5-fluorouracil and level of 5-fluorouracil in rodents. Gann 1979; 70: 209–14

    PubMed  CAS  Google Scholar 

  19. Taguchi T. Experience with UFT in Japan. Oncology (Huntingt) 1997; 11 Suppl. 10: 30–4

    CAS  Google Scholar 

  20. Pazdur R. Phase I and pharmacokinetic evaluations of UFT plus oral leucovorin. Oncology (Huntingt) 1997; 11 Suppl. 10: 35–9

    CAS  Google Scholar 

  21. Hoff PM, Lassere Y, Pazdur R. Tegafur/uracil + calcium folinate in colorectal cancer: double modulation of fluorouracil. Drugs 1999; 58 Suppl. 3: 77–83

    Article  PubMed  CAS  Google Scholar 

  22. Langer CJ. The role of tegafur/uracil in pulmonary malignancy. Drugs 1999; 58 Suppl. 3: 71–5

    Article  PubMed  CAS  Google Scholar 

  23. Ajani JA, Takiuchi H. Recent developments in oral chemotherapy options for gastric carcinoma. Drugs 1999; 58 Suppl. 3: 85–90

    Article  PubMed  CAS  Google Scholar 

  24. Lu Z, Zhang R, Diasio RB. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res 1993; 53: 5433–8

    PubMed  CAS  Google Scholar 

  25. Danenberg K, Salonga D, Park JM, et al. Dihydropyrimidine dehydrogenase and thymidylate synthase gene expressions identify a high percentage of colorectal tumors responding to 5-fluorouracil. Proc Am Soc Clin Oncol 1998; 17: 258A

    Google Scholar 

  26. Naguib FN, el Kouni MH, Cha S. Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Res 1985; 45: 5405–12

    PubMed  CAS  Google Scholar 

  27. Baccanari DP, Davis ST, Knick VC, et al. 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci USA 1993; 90: 11064–8

    Article  PubMed  CAS  Google Scholar 

  28. Spector T, Harrington JA, Porter DJT. 5-Ethynyluracil (776C85): inactivation of dihydropyrimidine dehydrogenase in vivo. Biochem Pharmacol 1993; 46: 2243–8

    Article  PubMed  CAS  Google Scholar 

  29. Cao S, Rustum YM, Spector T. 5-Ethynyluracil (776C85): modulation of 5-fluorouracil efficacy and therapeutic index in rats bearing advanced colorectal carcinoma. Cancer Res 1994; 54: 1507–10

    PubMed  CAS  Google Scholar 

  30. Schilsky RL, Burris H, Ratain M, et al. Phase I clinical and pharmacologic study of eniluracil plus 5-fluorouracil in patients with advanced cancer. J Clin Oncol 1998; 16: 1450–7

    PubMed  CAS  Google Scholar 

  31. Diasio RB. Improving 5-FU with a novel dihydropyrimidine dehydrogenase inactivator. Oncology (Huntingt) 1998; 12 Suppl. 4: 51–6

    CAS  Google Scholar 

  32. Shirasaka T, Shimamato Y, Ohsimo H, et al. Development of a novel form of an oral 5-fluorouracil derivative (S-l) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996; 7: 548–57

    Article  PubMed  CAS  Google Scholar 

  33. Shirasaka T, Shimamato Y, Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 1993; 53: 4004–9

    PubMed  CAS  Google Scholar 

  34. Shirasaka T, Nakano K, Takechi T, et al. Antitumor activity of IM tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 1996; 56: 2602–6

    PubMed  CAS  Google Scholar 

  35. Ohtsu A, Sakata Y, Horioshi N, et al. A phase II study of S-1 in patients with advanced gastric cancer. Proc Am Soc Clin Oncol 1998; 17: 262A

    Google Scholar 

  36. Baba H, Ohtsu A, Sakata Y, et al. Late phase II study of S-1 in patients with advanced colorectal cancer in Japan. Proc Am Soc Clin Oncol 1998; 17: 277A

    Google Scholar 

  37. Shirasaka T, Fujita F, Fujita M, et al. Antitumor activity and metabolism of BOF-A2, a new 5-fluorouracil derivative, with human cancers xenografted in nude mice. Gan To Kagaku Ryoho 1990; 17: 1871–6

    PubMed  CAS  Google Scholar 

  38. Sasaki T. New anti-cancer drugs for gastrointestinal cancers. Gan To Kagaku Ryoho 1997; 24: 1925–31

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, The University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA

    Robert B. Diasio (Professor of Pharmacology and Medicine, Chairman of the Department of Pharmacology and Toxicology and Director of the Division of Clinical Pharmacology)

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  1. Robert B. Diasio
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Correspondence to Robert B. Diasio.

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Diasio, R.B. Improving Fluorouracil Chemotherapy with Novel Orally Administered Fluoropyrimidines. Drugs 58 (Suppl 3), 119–126 (1999). https://doi.org/10.2165/00003495-199958003-00016

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