Investigational New Drugs

, Volume 18, Issue 4, pp 315–329 | Cite as

Conceptual Changes in Cancer Chemotherapy: From an Oral Fluoropyrimidine Prodrug, UFT, to a Novel Oral Fluoropyrimidine Prodrug, S-1, and Low-Dose FP Therapy in Japan

  • Tetsuhiko Shirasaka
  • Susumu Yamamitsu
  • Akihito Tsuji
  • Tetsuo Taguchi


The conventional concept in cancer chemotherapyconsiders that no efficacy can be attained withoutprovoking adverse reactions. We presented concretedescriptions based on a novel concept allowing us toemerge from the old one. Relief of adverse reactions,e.g., diarrhea, stomatitis, anorexia, and H&Fsyndrome, not only improves QOL of the patient butalso allows prolongation of the treatment periodwithout lowering patient compliance.

We describe in this paper a therapeutic modality which is basedon SRC (self-rescuing concept)featuring dual activity, i.e., effect-enhancingactivity and adverse reaction-reducing activity.

We present the theory and practice of S-1, anovel oral fluoropyrimidine anticancer agent designedto enhance anticancer activity and reducegastrointestinal toxicity through the deliberatecombination of the following components: an oralfluoropyrimidine agent tegafur; a DPD inhibitor (CDHP)which is more potent than uracil used in UFT; and anORTC inhibitor (Oxo) which localizes in thegastrointestinal tract. Furthermore, we refer tocombination therapy with 5-FU (CIV) and low-doseconsecutive CDDP in which CDDP was used as a modulatorof 5-FU and to the theory and practice of combinationtherapy with 5-FU (CVI) intermittent (Monday,Wednesday, and Friday) administration and low-doseCDDP consecutive administration in which a differencein cell cycle between gastrointestinal mucosal celland tumor cell or between bone marrow cell and tumorcell was utilized. We intend in future to combinethe abovementioned therapeutic modalities provokingless adverse reactions and being gentle to patientswith cancer in an effort to further increase theirlife expectancy.

biochemical modulation of 5-FU CDHP (DPD) inhibitor low-dose FP therapy oxo (potassium oxonate) S-1 UFT 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dushinsky R, Pleven E, Heidelberger C: The synthesis of 5-fluoropyrimidines. J Am Chem Soc 79: 4559–4560, 1957Google Scholar
  2. 2.
    Skipper HE, Schabel FM Jr, Wilcox WS: Experimental evaluation of potential anticancer agents. XIII on the criteria and kinetic associated with "curability" of experimental leukemia. Cancer Chemother Rep 35: 1–111, 1964Google Scholar
  3. 3.
    Houghton JA, Houghton PJ, Wooten RS: Mechanism of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2'-deoxyuridine. Cancer Res 39: 2406–2413, 1979Google Scholar
  4. 4.
    Schuetz JD, Wallace HJ, Diasio RB: 5-Fluorouracil incorporation into DNA of CF-1 mouse bone marrow cells as apossible mechanism of toxicity. Cancer Res. 44: 1358–1363, 1984Google Scholar
  5. 5.
    Fujii S, Shimamoto Y, Ohshima H, Imaoka T, Motoyama M, Fukushima M, Shirasaka T: Effect of the plasma concentration of 5-fluorouracil and the duration of continuous venous infusion of 5-fluorouracil with an inhibitor of 5-fluorouracil degradation on Yoshida sarcomas in rats. Jpn J Cancer Res 80: 167–172, 1989Google Scholar
  6. 6.
    Hilles S, Zhuk RA, Lidaks M: Analogues of pyrimidine nucleoside. N1-(α Furanydil) derivative of natural pyrimidine bases and their antimetabolites. Dokl Akad Nauk SSSR 176: 332–335, 1967 [Chem Abstrt, 69, 29664j (1968)]Google Scholar
  7. 7.
    Toide H, Akiyoshi H, Minato Y, Okuda H, Fujii S: Comparative studies on the mechanism of 2-(tetrahydrofuryl)-5-fluorouracil and 5-fluorouracil. Gann (Jpn J Cancer Res) 68: 553–560, 1977Google Scholar
  8. 8.
    Fujii S, Ikenaka K, Fukushima M, Shirasaka T: Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil. Gann (Jpn J Cancer Res) 69: 763–772, 1978Google Scholar
  9. 9.
    Pazdur R, Lassere Y, Rhodes V, Ajani JA, Sugarman SM, Patt YZ, Jones DV, Markowitz Jr A, Abbruzzese JL, Bready B, Levin B: PhaseTrial of Uracil and Tegafur Plus Oral Leucovorin: An Effective Oral Regimen in the Treatment ofMetasatic Colorectal Carcinoma. J Clin Oncol 12: 2296–2300, 1994Google Scholar
  10. 10.
    Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG: A prospective randomized comparison of continuous infusion fluorouracil with conventional bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic Oncology Program Study. J Clin Oncol 7: 425–432, 1989Google Scholar
  11. 11.
    The Meta-Analysis Group in cancer: efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16: 301–308, 1998Google Scholar
  12. 12.
    Tatsumi K, Fukushima M, Shirasaka T, Fujii S: Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rats liver extracts. Jpn J Cancer Res 78: 748–755, 1987Google Scholar
  13. 13.
    Schwartz PM, Handschumacher RE.: Selective antagonism of 5-fluorouracil cytotoxicity by 4-hydroxypyrazolopyrimidine (allopurinol) in vitro. Cancer Res 39: 3095–3101, 1979Google Scholar
  14. 14.
    Schwartz PM, Dunigan JM, Marsh JC, Handschumacher RE: Allopurinol modification of the toxicity and antitumor activity of 5-fluorouracil. Cancer Res 40: 1885–1889, 1980Google Scholar
  15. 15.
    Kroener JF, Saleh F, Howell SB: 5-FU and allopurinol: toxicity modulation and Phase II results in colon cancer. Cancer Treat Rep 66: 1133–1137, 1982Google Scholar
  16. 16.
    Wooley PV, Ayoob MJ, Smith FP Lokey JL, DeGreen P, Marantz A, Schein PS: A controlled trial of the effect of 4-hydroxypyrimidine (allopurinol) on the toxicity of a single bolus dose of 5-fluorouracil. J Clin Oncol 3: 103–109, 1985Google Scholar
  17. 17.
    Garewal HS, Ahmann FR, Alberts DS: Lack of inhibition by oxipurinol of 5-FU toxicity against human tumor cell lines. Cancer Treat Rep 67: 495–498, 1983Google Scholar
  18. 18.
    Shirasaka T, Shimamoto Y, Fukushima M: Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 53: 4004–4009, 1993Google Scholar
  19. 19.
    Granat P, Creasey W A, Calabresi P, Handschumacher R E: Investigations with 5-azaorotic acid, an inhibitor of the biosynthesis of pyrimidine de novo. Clin Pharmacol Ther 6: 436–447, 1965Google Scholar
  20. 20.
    Shirasaka T, Fukushima M, Shimamoto Y, Kimura K: Preclinical studies on S-1, a new oral tegafur plus modulators: Optimal molar ratio and antitumor activity. Recent Advance in Chemotherapy. Proc 18th Int Congress Chemother 927, 1994Google Scholar
  21. 21.
    Shirasaka T, Shimamoto Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, Fukushima M: Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anti-cancer Drugs 7: 548–557, 1996Google Scholar
  22. 22.
    Shirasaka T, Nakano K, Takechi T, Satake H, Uchida J, Fujioka A, Saito H, Okabe H, Oyama K, Takeda S, Unemi N, Fukushima M: Antitumor activity of 1M tegafur-0.4M 5-chloro-2,4-dihydroxypyridine-1M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 56: 2602–2606, 1996Google Scholar
  23. 23.
    Hirata K, Horikoshi N, Aiba K, Okazaki M, Denno R, Sasaki K, Nakano Y, Ishizuka H, Yamada Y, Uno S, Taguchi T, Shirasaka T: Pharmacokinetic Study of S-1,a Novel Oral Fluorouracil Antitumor Drug. Clin Cancer Res 5: 2000–2005, 1999Google Scholar
  24. 24.
    Sugimachi K, Maehara Y, Horikoshi N, Shimada Y, Sakata Y, Mitachi Y, Taguchi T: An early Phase II study of oral S-1, a newly developed 5-fluorouracil derivative for treating patients with advanced and recurrent gastrointestinal cancer. Oncology 57: 202–210, 1999Google Scholar
  25. 25.
    Koizumi W, Kurihara M, Nakano S, Hasegawa K: Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. Oncology in pressGoogle Scholar
  26. 26.
    Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y, Taguchi T: Late Phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1M tegafur-0.4M gimestat-1M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 34: 1715–1720, 1998Google Scholar
  27. 27.
    Scanlon KJ, Safirstein RL, Thies H, Gross TB, Waxman S, Guttenplan JB: Inhibition of amino acid transport by cisdiaminedichloroplatinum (II) derivatives in L-1210 murine leukemia cell. Cancer Res 43: 4211–4215, 1983Google Scholar
  28. 28.
    Shirasaka T, Shimamoto Y, Ohshimo H, Saito H, Fukushima M: Metabolic basis of the synergistic antitumor activities of 5-fluorouracil and cisplatin in rodent tumor models in vivo. Cancer Chemother Pharmacol 132: 167–172, 1993Google Scholar
  29. 29.
    Omura K, Misaki T, Hashimoto T, Kanehira E, Watanabe T, Ishida F, Watanabe Y, Shirasaka T: Change in folate concentration in Yoshida sarcoma after administration of leucovorin or cisplatin. Cancer Chemother Pharmacol 35: 183–187, 1995Google Scholar
  30. 30.
    Shirasaka T, Aiba K, Araki H, Suzuki M, Terashima M Mikami Y: Combination Therapy of Continuous Venous Infusion (CVI) of 5-FU and Low dose Consecutive Cisplatin(CDDP), and the New Oral Anti-cancer Drug S-1 for Advanced Gastro-Intestinal Cancer. Jpn J Cancer Chemother 26: 456–466 1999Google Scholar
  31. 31.
    Mizutani Y, Yoshida O, Bonavida B: Sensitization of human bladder cancer cells to Fas-mediated cytotoxicity by cis-diamminedichloroplatinum. J Urol 160: 561–570, 1998Google Scholar
  32. 32.
    Mizutani Y, Wu XX, Yoshida O, Shirasaka T, Bonavida B: Chemoimmunosensitization of the T24 human bladder cancer line to Fas-madiated cytotoxicity and apoptosis by cisplatin and 5-fluorouracil Oncol Rept 6: 979–982, 1999Google Scholar
  33. 33.
    Nishiyama M, Yamamoto W, Park J-S, Okamoto R, Hanaoka H, Takano H, Saito N, Matsukawa M, Shirasaka T, Kurihara M: Low-dose cisplatin and 5-fluorouracil in combination can repress increased gene expression of cellular resistance determinants to themselves. Clin Cancer Res 5: 2620–2628, 1999Google Scholar
  34. 34.
    Tsuji A, Morita S, Horimi T, Takasaki M, Takahashi I, Shirasaka T: Ambulatory and domiciliary cancer chemotherapy with forearm implant catheter system and low-dose CDDP+5-FU therapy. Jpn J Cancer Chemother 26: 326–332, 1999Google Scholar
  35. 35.
    Kondo K, Murase M, Kodera Y, Akiyama S, Ito K, Yokoyama Y, Takagi H, Shirasaka T: Feasibility study on protracted infusional 5-fluorouracil and consecutive low-dose cisplatin for advanced gastric cancer. Oncology 53: 64–67, 1996Google Scholar
  36. 36.
    Chung Y, Yamashita Y, Matsuoka T, Nakata T, Onoda N, Maeda K, Sawada K, Kato Y, Shirasaka T, Sowa M: Continuous infusion of 5-fluorouracil and low dose cisplatin infusion for the treatment of advanced and recurrent gastric adenocarcinoma. Cancer 80: 1–7, 1997Google Scholar
  37. 37.
    Sasaki K, Hirata K, Takasaka,H, Hiraike N, Katsuramaki T, Oikawa I, Denno R, Yamamitsu, S, Shirasaka T: Combination chemotherapy of continuous infusion 5-FU and CDDP for advanced colorectal cancer: A Sapporo Cancer Study (SACS) trial. Proc ASCO 16: 269a 1997Google Scholar
  38. 38.
    Lipkin M, Sherlock P, Bell B: Cell proliferation kinetics in the gastrointestinal tract of man II cell renewal stomach, ileum, colon, and rectum. Gastroenterology 45: 721–779, 1963Google Scholar
  39. 39.
    Clarkson B, Ota K, Ohkita T, O'Connor A: Kinetics of proliferation of cancer cell in neoplastic effusions in man. Cancer 8: 1179–1213, 1965Google Scholar
  40. 40.
    Sugiyama K, Mizunuma N, Shibata H, Ito Y, Takahashi S, Horikoshi N, Aiba K, Shirasaka T: Intermittent exposure of 5-fluorouracil, on and off schedule, shows high cytotoxicity in a colon cancer cell line. Proc AACR 40: 2644a 1999Google Scholar
  41. 41.
    Hirata K, Yamamitsu S, Tsuji A, Shirasaka T, Mukaiya M, Oikawa I, Kimura H, Sasaki K, Dennno R: Biochemical modulation of 5-FU-effect of low-dose CDDP. Jpn J Cancer Chemother 26: 467–475, 1999Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Tetsuhiko Shirasaka
    • 1
  • Susumu Yamamitsu
    • 2
  • Akihito Tsuji
    • 3
  • Tetsuo Taguchi
    • 4
  1. 1.Lab. Pathogenic Biochemistry in MedicineTaiho Pharmaceutical Co., Ltd.TokyoJapan
  2. 2.Sapporo Tsukisamu HospitalSapporoJapan
  3. 3.Kochi Municipal Center HospitalKochiJapan
  4. 4.Japanese Society for Cancer ChemotherapyOsakaJapan

Personalised recommendations