Advertisement

Investigational New Drugs

, Volume 18, Issue 4, pp 355–363 | Cite as

Capecitabine

  • Daniel R. Budman
Article

Abstract

Drug development has undergone rapid shifts inmethodology and the use of rationally derived agents which eithertarget specific tissues or molecules such as receptors orenzymatic sites. Capecitabine is a rationally derived prodrug of5-fluorouracil which is based upon the known high concentrationof the enzyme thymidine phosphorylase in many human tumors. Thefirst prodrug designed to exploit this biochemical finding was5-DFUR which allowed cytotoxic 5-fluorouracil to bepreferentially concentrated in tumors. Unfortunately, in man thisagent was associated with significant gastrointestinal toxicity.Further manipulation of this molecular resulted in capecitabinewhich is a relatively inert prodrug, undergoes three enzymaticsteps, and offers the potential of less gastrointestinaltoxicity. Phase I trials have examined several schedules with thedivided oral daily × 14 schedule every 3 weeks as thepreferred phase II and phase III dosing method. This agentdemonstrates significant antitumor effect in diseases known tobe responsive to fluoropyrimidines. Further study is needed todetermine whether capecitabine has a broader spectrum of actionthus affecting other tumor types than 5-fluorouracil. Major doselimiting toxicities have been hand foot syndrome,nausea/vomiting, and diarrhea.

capecitabine enzymatic activation prodrug 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bodor N, Buchwald P, Huang M: Computer-assisted design of new drugs based upon retrometabolic concepts. SAR QSAR Environ Res 8: 41–92, 1998Google Scholar
  2. 2.
    Heidelberger C: Fluorinated pyrimidines: A new class of tumor-inhibitory compounds. Nature 179: 663–666, 1957Google Scholar
  3. 3.
    Takimoto C, Yee L, Venzon D, Schuler B, Grollman F, Chabuk C, Hamilton J, Chen A, Allegra C, Grem J: High inter-and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion. Clin Cancer Res 5: 1347–1352, 1999Google Scholar
  4. 4.
    Cook A, Holman M, Krammer M, Trown P: Fluorinated pyrimidine nucleotides. 3. Synthesis and antitumor activity of a series of 5'-deoxy-5-fluoropymidine nucleotides. J Med Chem 22: 1330–1335, 1979Google Scholar
  5. 5.
    Ishitsuka H, Miwa M, Takemoto K, Fukuoka K, Itoga A, Maruyama H: Role of uridine phosphorylase for antitumor activity of 5'-deoxy-S-fluorouridine. Gann 71: 112–123, 1980Google Scholar
  6. 6.
    Bollag W, Hartmann H: Tumor inhibitory effects of a new fluorouracil derivative: 5'-deoxy-5-fluorouridine. Eur J Cancer 16: 427–432, 1980Google Scholar
  7. 7.
    Suzuki S, Hongu Y, Fukazawa H, Ichihara, S, Shimizu H: Tissue distribution of 5'-deoxy-5-fluorouridine and derived 5-fluorouracil in tumor bearing mice and rats. Gann 71: 238–245, 1980Google Scholar
  8. 8.
    De Cesare M, Pratesi G, De Braud F, Zuninno F, Stampino C: Remarkable antitumor activity of 5'-deoxy-5-fluorouridine in human colorectal xenografts. AntiCancer Res 14: 549–554, 1994Google Scholar
  9. 9.
    Ishikawa T, Ura M, Yamamoto T, Tanaka Y, Ishitsuka H: Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5'-deoxy-5-fluorouridine. Int J Cancer 61: 516–521, 1995Google Scholar
  10. 10.
    van der Heyden S, Gheuens E, van de Vrie W, Van Bockstaele D, Van Oosterom A, Eggermont A, De Bruijn EA: Y-Deoxy-5-fluorouridine increases daunorubicin uptake in multidrug-resistant cells and its activity is related with P-gp 170 expression. Jpn J Cancer Res 85: 13–16, 1994Google Scholar
  11. 11.
    Takiguchi N, Nakajima N, Saitoh N, FuJimoto S, Nakazato H: A phase III study comparing oral 5'-deoxy-5-fluorouridine and oral 5-fluorouracil in patients with curative gastric cancer (Meeting Abstract). Proc Annu Meet Am Soc Clin Oncol 18: 936a, 1999Google Scholar
  12. 12.
    Budman D, Lichtman S: Investigational Drugs, in Perry M (ed): The Chemotherapy Sourcebook (ed 2). Baltimore, Williams & Wilkins, 1996, pp 479–558Google Scholar
  13. 13.
    Meropol N, Creaven P, Petrelli N: Metastatic colorectal cancer: Advances in biochemical modulation and new drug development. Semin Oncol 22: 509–524, 1995Google Scholar
  14. 14.
    Ninomlya Y, Miwa M, Eda H, et al.: Comparative antitumor activity and intestinal toxicity of 5'-deoxy-5-fluorouradine and its prodrug trimethoxybenzoyl-5′-deoxyflourocytidine. Jpn Cancer Res 81: 188–195, 1990Google Scholar
  15. 15.
    Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda 1, Ishitsuka H: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34: 1274–1281, 1998Google Scholar
  16. 16.
    Fox SB, Westwood M, Moghaddam A, Comley M, Turley H, Whitehouse RM, Bicknell R, Gatter KC, Harris AL: The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium. Br J Cancer 73: 275–280, 1996Google Scholar
  17. 17.
    Ishikawa T, Utoh M, Sawada N, Nishida M, Fukase Y, Sekiguchi F, Ishitsuka H: Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbarnate, in human cancer xenografts. Bio Chem Pharmacol 55: 1091–1097, 1998Google Scholar
  18. 18.
    Cao S, Lu K, Ishitsuka H, Rusturn YM: Antitumor efficacy of capecitabine against fluorouracil-sensitive and-resistant tumors (Meeting Abstract), Proc Annu Meet Am Soc Clin Oncol, 16: 795a, 1997Google Scholar
  19. 19.
    Ishikawa T, Sekiguchi F, Fukase Y, Sawada N, Ishitsuka H: 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 58: 685–690, 1998Google Scholar
  20. 20.
    Koizumi W, Saigenji K, Nakamaru N, Okayasu I, Kurihara M: Prediction of response to 5'-deoxy-5-fluorouridine (50DFUR) in patients with inoperable advanced gastric cancer by immunostaining of thymidine phosphorylase/plateletderived endothelial cell growth factor. Oncology 56: 215–222, 1999Google Scholar
  21. 21.
    Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H: Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 4: 1013–1019, 1998Google Scholar
  22. 22.
    Ishitsuka H, Ishikawa T, Fukase Y, Sawada N, Tanaka Y, Ouchi K, Yoshikubo T, Nishida M: Capecitabine and the dThdPase upregulators IFNgamma or Taxol showed synergistic activity in human cancer xenografts (Meeting abstract), Proc Annu Meet Am Assoc Cancer Res 37..2766a, 1996Google Scholar
  23. 23.
    Makower D, Wadler S, Haynes H, Schwartz EL: Interferon induces thymidine phosphorylase/platelet-derived endothelial cell growth factor expression in vivo. Clin Cancer Res 3: 923–929, 1997Google Scholar
  24. 24.
    Eda H, FuJimoto, K, Watanabe S, Ura M, Hino A, Tanaka Y, Wada K, Ishitsuka H: Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5'-deoxy-5-fluorouridine. Cancer Chemother Pharmacol 32: 333–338, 1993Google Scholar
  25. 25.
    Budman DR, Meropol NJ, Reigner B, Creaven PJ, Lichtnian SM, Berghorn E, Behr J, Gordon RJ, Osterwaider B, Griffin T: Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine. J Clin Oncol 16: 1795–1802, 1998Google Scholar
  26. 26.
    Mackean M, Planting A, Twelves C, Schellens J, Allman D, Osterwalder B, Reigner B, Griffin T, Kaye S, Verweij J: Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol 16: 2977–2985, 1998Google Scholar
  27. 27.
    Cassidy J, Dirix L, Bissett D, Reigner B, Griffin T, Allman D, Osterwalder B, Van Oosterom AT. A Phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors. Clin Cancer Res 4: 2755–2761, 1998Google Scholar
  28. 28.
    Bajetta E, Carnaghi C, Somma L, Stampino CG: A pilot safety study of capecitabine, a new oral fluoropyrimidine, in patients with advanced neoplastic disease. Tumori 82: 450–452, 1996Google Scholar
  29. 29.
    Villalona-Calero M, Weiss G, Burris H, Kraynak M, Rodriques G, Drengler R, Eckhardt S, Reigner B, Maczygemba J, Burger H, Griffin T, Von Hoff D, Rowinsky E: Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies. J Clin Oncol 17: 1915–1925, 1999Google Scholar
  30. 30.
    Olencki T, Pratt S, Budd G, Peereboom D, McClain D, Bukowski R: Phase I trial of capecitabine and subcutaneous interferon-alpha in renal cell carcinoma (Meeting Abstract). Proc Annu Meet Am Soc Clin Oncol 18: 855a, 1999Google Scholar
  31. 31.
    Graham M, Kaye S: New approaches in preclinical and cancer pharmacokinetics, in Workman P, Graham M (eds): Cancer Surveys, Pharmacokinetics and Cancer Chemotherapy. Cold Spring Harbor, Cold Spring Harbor Laboratory Press, 1993, pp 27–49Google Scholar
  32. 32.
    Reigner B, Jones R, Cassidy J, Schuller J, Goggin T, Jones D, Twelves C: Hepatic dysfunction due to liver metastasis does not affect the bioactivation of Xeloda (Meeting Abstract). Proc Annu Meet Am Soc Clin Oncol 17: 863a, 1998Google Scholar
  33. 33.
    Reigner B, Clive S, Cassidy J, Jodrell D, Schulz R, Goggin T, Banken L, Roos B, Utoh M, Mulligan T, Weidekamm E: Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients. Cancer Chemother Pharmacol 43: 309–315, 1999Google Scholar
  34. 34.
    Reigner B, Verweij J, Dirix L, Cassidy J, Twelves C, Allman D, Weidekamm E, Roos B, Banken L, Utoh M, Osterwalder B: Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res 4: 941–948, 1998Google Scholar
  35. 35.
    Schuller J, Cassidy J, Reigner 13G, Durston S, Roos B, Ishitsuka H, Utoh M, Dumont E: Turnor selectivity of Xeloda in colorectal cancer patients (Meeting abstract), Proc Annu Meet Am Soc Clin Oncol, 1998, pp 797aGoogle Scholar
  36. 36.
    Blum JL, Jones SE, Buzdar AU, LoRusso PM, Ktiter I, Vogel C, Osterwalder B, Burger HU, Brown CS, Griffin T: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17: 485–493, 1999Google Scholar
  37. 37.
    Saeki T, Takashima S: [Mechanism and possible biochemical modulation of capecitabine (Xeloda), a newly generated oral fluoropyrimidine]. Gan 26: 447–455, 1999Google Scholar
  38. 38.
    Findlay M, Van Cutsem E, Kocha W, Allman D, Laffranchi B, Griffin T, Osterwalder B, Dalley D, Pazdur R, Verweij J: A randomized phase II study of Xeloda (capecitabine) in patients with advanced colorectal cancer (Meeting abstract), Proc Annu Meet Am Soc Clin Oncol, 1997, pp 798aGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Daniel R. Budman
    • 1
  1. 1.Section of Experimental Therapeutics, Don Monti Division of Oncology, North Shore University HospitalNew York University School of MedicineManhassetUSA

Personalised recommendations