Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1999 Apr;90(4):432–438. doi: 10.1111/j.1349-7006.1999.tb00766.x

p53 Status Predicts the Efficacy of Postoperative Oral Administration of Tegafur for Completely Resected Non‐small Cell Lung Cancer

Fumihiro Tanaka 1, Kazuhiro Yanagihara 1, Yohsuke Ohtake 1, Ryou Miyahara 1, Youzou Kawano 1, Tatsuo Fukuse 1, Shigeki Hitomi 1, Hiromi Wada 1,
PMCID: PMC5926087  PMID: 10363582

Abstract

Although postoperative adjuvant therapy for non‐small cell lung cancer (NSCLC) had not been reported to be effective, it has been reported recently that oral administration of tegafur (1‐[2‐tetrahydrofuryl]‐5‐fluorouracil, FT) may improve the postoperative prognosis. In the present paper, to examine whether p53 status affects the efficacy of FT as postoperative adjuvant chemotherapy for NSCLC, a total of 236 consecutive patients with completely resected pathologic stage I–IIIa NSCLC were retrospectively reviewed. p53 status was determined by immunohistochemical staining. For all patients, the 5‐year survival rate of patients with FT administration (FT group) was 78.1%, being significantly higher than that (69.1%) of patients without FT administration (control group) (P=0.046). For patients without immunohistochemical evidence of p53 overexpression, the 5‐year survival rate in the FT group was 87.1%, being significantly higher than that (74.0%) in the control group (P=0.036). This demonstrates an improvement of postoperative prognosis by FT administration. On the other hand, for patients with p53 overexpression, there was no significant difference in the postoperative prognosis between the FT group and the control group (5‐year survival rate 63.2% and 60.1%, respectively; P=0.514), demonstrating that FT administration was not effective for these patients. In conclusion, p53 status may be useful for predicting the efficacy of postoperative adjuvant chemotherapy using FT. A prospective randomized study stratified by p53 status is needed to clarify the effect of postoperative FT administration.

Keywords: p53, Tegafur, Non‐small cell lung cancer

Full Text

The Full Text of this article is available as a PDF (85.2 KB).

Part of this article appeared in Proc. ASCO, 16, 485a (1997).

REFERENCES

  • 1).Shields , T. W.Surgical treatment of non‐small cell bronchial carcinoma . In “ General Thoracic Surgery ” 4th Ed. , ed. Shields T. W. , pp . 1159 – 1187 ( 1994. ). Williams & Wilkins, Inc. , Philadelphia ). [Google Scholar]
  • 2).Ihde , D. , Ball , D. , Arriagada , R. , Bathelemy , N. , Benner , S. , Bonner , J. , Bureau , G. , Crino , L. , Deneffe , G. , Emami , B. , Feld , R. , Joseph , D. , Paccagnella, Rocmans , P. and van Houtte , P.Postoperative adjuvant therapy for non‐small cell lung cancer: a consensus report . Lung Cancer , 11s , 15 – 17 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 3).Blokhina , N. G. , Vozny , E. K. and Garin , A. M.Results of treatment of malignant tumors with tegafur . Cancer , 30 , 390 – 392 ( 1972. ). [DOI] [PubMed] [Google Scholar]
  • 4).Ansfield , F. J. , Kallas , G. J. and Singson , J. P.Phase I–II studies of oral tegafur (futrafur) . J. Clin. Oncol. , 1 , 107 – 110 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 5).Tanaka , F. , Yanagihara , K. , Wada , H. and Hitomi , S.Advantage of postoperative oral administration of tegafur (FT) for completely resected p‐stage I–IIIa non‐small cell lung cancer (NSCLC) . Proc. ASCO , 15 , 393 ( 1996. ). [Google Scholar]
  • 6).Fujii , S. , Ikenaka , K. , Fukushima , M. and Shirasaka , T.Effect of uracil and its derivatives on antitumor activity of 5‐fluorouracil and 1‐(2‐tetrahydrofuryl)‐5‐fluorouracil . Gann , 69 , 763 – 772 ( 1978. ). [PubMed] [Google Scholar]
  • 7).Pazdur , R. , Lassere , Y. , Rhodes , V. , Ajani , J. A. , Sugarman , S. M. , Patt , Y. Z. , Jones , D. V. , Jr. , Markowitz , A. B. , Abbruzzese , J. L. , Bready , B. and Levin , B.Phase II trial of uracil and tegafur plus oral leucovorin: effective oral regimen in the treatment of metastatic colorectal carcinoma . J. Clin. Oncol. , 12 , 2296 – 2300 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 8).Muggia , F. M. , Wu , X. , Spicer , D. , Groshen , S. , Jeffers , S. , Leichman , C. G. , Leichman , L. and Chan , K. K.Phase I and pharmacokinetic study of oral UFT, a combination of the 5‐fluorouracil prodrug tegafur and uracil . Clin. Cancer Res. , 2 , 1461 – 1467 ( 1996. ). [PubMed] [Google Scholar]
  • 9).Wada , H. , Hitomi , S. , ter amatsu , T.and West Japan Study Group for Lung Cancer Surgery. Adjuvant chemotherapy after complete resection in non‐small‐cell lung cancer . J. Clin. Oncol. , 14 , 1048 – 1054 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 10).The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan). A randomized trial of postoperative adjuvant chemotherapy in non‐small cell lung cancer (The second cooperative study) . Eur. J. Surg. Oncol. , 21 , 1995. , 69 – 77 ). [PubMed] [Google Scholar]
  • 11).Pinedo , H. M. and Peter , F. J.Fluorouracil: biochemistry and pharmacology . J. Clin. Oncol. , 6 , 1653 – 1664 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 12).Lokich , J. , Ahlgren , J. D. , Gullo , J. J. , Philips , J. A. and Fryer , J. G.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. , 7 , 425 – 432 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 13).Levine , A. J. , Monmand , J. and Finlay , C. A.The p53 tumor suppressor gene . Nature , 351 , 453 – 456 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 14).Vogelstein , B. and Kinzler , K. W.p53 function and dysfunction . Cell , 70 , 523 – 526 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 15).Greenblatt , M. S. , Bernnett , W. P. , Hollstein , M. and Harris , C. C.Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis . Cancer Res. , 54 , 4855 – 4878 ( 1994. ). [PubMed] [Google Scholar]
  • 16).Quinlan , D. C. , Davidson , A. G. , Summers , C. L. , Warden , H. E. and Doshi , H. M.Accumulation of p53 protein correlates with poor prognosis in human lung cancer . Cancer Res. , 52 , 4828 – 4831 ( 1992. ). [PubMed] [Google Scholar]
  • 17).Morkve , O. , Halvorsen , O. J. , Skjaerven , R. , Stangeland , L. , Gulsvik , A. and Laerum , O. D.Prognostic significance of p53 protein expression and DNA ploidy in surgically treated non‐small cell lung carcinomas . Anticancer Res. , 13 , 571 – 578 ( 1993. ). [PubMed] [Google Scholar]
  • 18).Passlick , B. , Izbicki , J. R. and Riethmuller , G.p53 in non‐small cell lung cancer . J. Natl. Cancer Inst. , 86 , 801 – 802 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 19).Mitsudomi , T. , Oyama , T. , Kusano , T. , Osaki , T. , Nakanishi , R. and Shirakusa , T.Mutations of the p53 gene as a predictor of poor prognosis in patients with non‐small cell lung cancer . J. Natl. Cancer Inst. , 85 , 2018 – 2023 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 20).Bergh , J. , Norberg , N. , Sjogren , S. , Lindgren , A. and Holmberg , L.Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy . Nat. Med. , 1 , 1029 – 1034 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 21).Rusch , V. , Klimstra , D. , Venkartraman , E. , Oliver , J. , Martini , N. , Gralla , R. , Kris , M. and Dmitrovsky , E.Aberrant p53 expression predicts clinical resistance to cisplatin‐based chemotherapy in locally advanced non‐small cell lung cancer . Cancer Res. , 55 , 5038 – 5042 ( 1995. ). [PubMed] [Google Scholar]
  • 22).Wada , H. , Tanaka , F. , Yanagihara , K. , Ariyasu , T. , Fukuse , T. , Yokomise , Y. , Inui , K. , Mizuno , H. , Ike , O. and Hitomi , S.Time trends and survival after surgery for primary lung cancer during 1976–1990 . J. Thorac. Cardiovasc. Surg. , 112 , 349 – 355 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 23).Mountain , C. F.A new international staging system for lung cancer . Chest , 89 , 225s – 233s ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 24).World Health Organization. The World Health Organization histological typing of lung tumors . Second edition . Am. J. Clin. Pathol. , 77 , 1982. , 123 – 136 ). [DOI] [PubMed] [Google Scholar]
  • 25).Tanaka , F. , Miyahara , R. , Ohtake , Y. , Yanagihara , K. , Fukuse , T. , Hitomi , S. and Wada , H.Lewis Y antigen expression and postoperative survival in nonsmall cell lung cancer . Ann. Thorac. Surg. , 66 , 1745 – 1750 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 26).Holmgren , L. , O'Reilly , M. S. and Folkman , J.Dormancy of micrometastasis: balanced proliferation and apoptosis in the presence of angiogenesis suppression . Nat. Med. , 1 , 149 – 153 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 27).Barry , M. A. , Behnke , C. A. and Eastman , A.Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia . Biochem. Pharmacol. , 40 , 2353 – 2362 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 28).Kuerbitz , S. J. , Plunkett , B. S. , Walsh , W. V. and Kasten , M. B.Wild‐type p53 is a cell cycle checkpoint determinant following irradiation . Proc. Natl. Acad. Sci. USA , 89 , 7491 – 7495 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29).Yonish‐Rouach , E. , Resnitzky , D. , Lotem , J. , Sachs , L. , Kimchi , A. and Oren , M.Wild‐type p53 induces apoptosis of myeloid leukemic cells that is inhibited by interleukin‐6 . Nature , 352 , 345 – 347 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 30).Symonds , H. , Krall , L. , Remington , L. , Saenz‐Robles , M. , Lowe , S. , Jacks , T. and Dyke , T. V.p53‐dependent apoptosis suppresses tumor growth and progression in vivo . Cell , 78 , 1994. , 703 – 711 ). [DOI] [PubMed] [Google Scholar]
  • 31).Lowe , S. W. , Bodis , S. , McClatchey , A. , Remington , L. , Ruley , H. E. , Fischer , D. E. , Housman , D. E. and Jacks , T.p53 status and the efficacy of cancer therapy . Science , 266 , 807 – 810 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 32).Matlashewski , G. , Banks , L. , Pim , D. and Crawford , L.Analysis of human p53 proteins and mRNA levels in normal and transformed cells . Eur. J. Biochem. , 154 , 665 – 672 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 33).Iggo , R. , Gatter , K. , Barter , J. , Lane , D. and Harris , A. L.Increased expression of mutant form of p53 oncogene in primary lung cancer . Lancet , 335 , 675 – 679 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 34).Carbone , D. P. , Mitsudori , T. , Chiba , I. , Piantadosi , S. , Rusch , V. , Nowak , J. A. , McIntire , D. , Slamon , D. , Gazdar , A. and Minna , J.p53 immunostaining positivity is associated with reduced survival and imperfectly correlated with gene mutations in resected non‐small cell lung cancer. A preliminary report of LCSG 871 . Chest , 106 , 377s – 381s ( 1994. ). [PubMed] [Google Scholar]
  • 35).Righetti , S. C. , Torre , G. D. , Pilotti , S. , Menard , S. , Ottone , F. , Colnaghi , M. I. , Pierotti , M. A. , Lavarino , C. , Cornarotti , M. , Oriana , S. , Bohm , S. , Bresciani , G. L. , Spatti , G. and Zunino , F.A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin‐based chemotherapy in advanced ovarian carcinoma . Cancer Res. , 56 , 689 – 693 ( 1996. ). [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES