Skip to main content

Advertisement

SpringerLink
Log in

Schedule-dependent cytotoxicity of 5-fluorouracil and irinotecan in a colon cancer cell line

  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Our aim was to clarify the significance of widely accepted irinotecan (CPT-11)/5-fluorouracil (5-FU) combinations in colon cancer by investigating their sequential effect.

Methods

The sequential effect of CPT-11/5-FU in two colon cancer cell lines, LoVo and SW480, was evaluated by WST-8 colorimetric assay. The cell cycle distributions of each drug were analyzed by flow cytometry, and then the chemoresistant mechanisms and expression of a drug transporter (MDR1), the bcl-2 apoptotic pathway, metabolizing enzymes [carboxylesterase (CE), dihydropyrimidine dehydrogenase], and target enzymes (topoisomerase I, thymidine synthase) associated with sequence-dependent cytotoxicity were examined.

Results

The cytotoxicity of 5-FU (10, 100, 1000 µM) followed by CPT-11 (1 µM) was significantly greater than that of CPT-11 (1 µM) followed by 5-FU (10, 100, 1000 µM) (P < 0.05). Reverse transcription-polymerase chain reaction analysis revealed that exposure to 5-FU downregulated both MDR1 and bcl-2 mRNA and simultaneously upregulated CE2 mRNA expression, suggesting enhancement of subsequent CPT-11 cytotoxicity.

Conclusions

The cytotoxic effects of the CPT-11/5-FU combinations were shown to be schedule-dependent in human colon cancer cells. The findings suggest that 5-FU followed by CPT-11 administration might be the optimal sequence for CPT-11/5-FU treatment of advanced colon cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Y Pommier A Tanizawa KW Kohn (1994) ArticleTitleMechanisms of topoisomerase I inhibition by anticancer drugs Adv Pharmacol 29 73–92 Occurrence Handle10.1016/S1054-3589(08)61132-1

    Article  Google Scholar 

  2. YH Hsiang MG Lihou LF Liu (1989) ArticleTitleArrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin Cancer Res 15 5077–82

    Google Scholar 

  3. C Holm JM Covey D Kerrigan Y Pommier (1989) ArticleTitleDifferential requirement of DNA replication for the cytotoxicity of DNA topoisomerase I and II inhibitors in Chinese hamster DC3F cells Cancer Res 15 6365–8

    Google Scholar 

  4. CG Shin RM Snapka (1990) ArticleTitleExposure to camptothecin breaks leading and lagging strand simian virus 40 DNA replication forks Biochem Biophys Res Commun 16 135–40 Occurrence Handle10.1016/0006-291X(90)91684-K

    Article  Google Scholar 

  5. SH Kaufmann (1998) ArticleTitleCell death induced by topoisomerase-targeted drugs: more questions than answers Biochim Biophys Acta 1 195–211

    Google Scholar 

  6. ML Rothenberg JR Eckardt JG Kuhn HA Burris Suffix3rd J Nelson SG Hilsenbeck et al. (1996) ArticleTitlePhase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer J Clin Oncol 14 1128–35 Occurrence Handle8648367 Occurrence Handle1:CAS:528:DyaK28XisFyksbY%3D

    PubMed  CAS  Google Scholar 

  7. HC Pitot DB Wender MJ O'Connell G Schroeder RM Goldberg J Rubin et al. (1997) ArticleTitlePhase II trial of irinotecan in patients with metastatic colorectal carcinoma J Clin Oncol 15 2910–9 Occurrence Handle9256135 Occurrence Handle1:CAS:528:DyaK2sXls1Smurg%3D

    PubMed  CAS  Google Scholar 

  8. M Fukuoka H Niitani A Suzuki M Motomiya K Hasegawa Y Nishiwaki et al. (1992) ArticleTitleA phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small-cell lung cancer J Clin Oncol 10 16–20 Occurrence Handle1309380 Occurrence Handle1:STN:280:By2D1M3gsFw%3D

    PubMed  CAS  Google Scholar 

  9. H Bleiberg (1999) ArticleTitleCPT-11 in gastrointestinal cancer Eur J Cancer 35 371–9 Occurrence Handle10448285 Occurrence Handle10.1016/S0959-8049(98)00423-7 Occurrence Handle1:CAS:528:DyaK1MXisVGqsrc%3D

    Article  PubMed  CAS  Google Scholar 

  10. LB Saltz JV Cox C Blanke LS Rosen L Fehrenbacher MJ Moore et al. (2000) ArticleTitleIrinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group N Engl J Med 28 905–14 Occurrence Handle10.1056/NEJM200009283431302

    Article  Google Scholar 

  11. JY Douillard D Cunningham AD Roth M Navarro RD James P Karasek et al. (2000) ArticleTitleIrinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial Lancet 25 1041–7 Occurrence Handle10.1016/S0140-6736(00)02034-1

    Article  Google Scholar 

  12. S Mullany PA Svingen SH Kaufmann C Erlichman (1998) ArticleTitleEffect of adding the topoisomerase I poison 7-ethyl-10-hydroxycamptothecin (SN-38) to 5-fluorouracil and folinic acid in HCT-8 cells: elevated dTTP pools and enhanced cytotoxicity Cancer Chemother Pharmacol 42 391–9 Occurrence Handle9771954 Occurrence Handle10.1007/s002800050835 Occurrence Handle1:CAS:528:DyaK1cXmt1Ols7s%3D

    Article  PubMed  CAS  Google Scholar 

  13. YP Tsao P D'Arpa LF Liu (1992) ArticleTitleThe involvement of active DNA synthesis in camptothecin-induced G2 arrest: altered regulation of p34cdc2/cyclin B Cancer Res 1 1823–9

    Google Scholar 

  14. DR Mans I Grivicich GJ Peters G Schwartsmann (1999) ArticleTitleSequence-dependent growth inhibition and DNA damage formation by the irinotecan-5-fluorouracil combination in human colon carcinoma cell lines Eur J Cancer 35 1851–61 Occurrence Handle10674003 Occurrence Handle10.1016/S0959-8049(99)00222-1 Occurrence Handle1:CAS:528:DyaK1MXntVeqsrw%3D

    Article  PubMed  CAS  Google Scholar 

  15. V Pavillard P Formento P Rostagno JL Formento JL Fischel M Francoual et al. (1998) ArticleTitleCombination of irinotecan (CPT11) and 5-fluorouracil with an analysis of cellular determinants of drug activity Biochem Pharmacol 15 1315–22 Occurrence Handle10.1016/S0006-2952(98)00205-6

    Article  Google Scholar 

  16. S Cao YM Rustum (2000) ArticleTitleSynergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: role of drug sequence and dose Cancer Res 15 3717–21

    Google Scholar 

  17. RG Azrak S Cao HK Slocum K Toth FA Durrani MB Yin et al. (2004) ArticleTitleTherapeutic synergy between irinotecan and 5-fluorouracil against human tumor xenografts Clin Cancer Res 1 1121–9 Occurrence Handle10.1158/1078-0432.CCR-0913-3

    Article  Google Scholar 

  18. S Guichard D Cussac I Hennebelle R Bugat P Canal (1997) ArticleTitleSequence-dependent activity of the irinotecan–5FU combination in human colon-cancer model HT-29 in vitro and in vivo Int J Cancer 73 729–34 Occurrence Handle9398054 Occurrence Handle10.1002/(SICI)1097-0215(19971127)73:5<729::AID-IJC20>3.0.CO;2-# Occurrence Handle1:CAS:528:DyaK2sXns1Kkuro%3D

    Article  PubMed  CAS  Google Scholar 

  19. S Guichard I Hennebelle R Bugat P Canal (1998) ArticleTitleCellular interactions of 5-fluorouracil and the camptothecin analogue CPT-11 (irinotecan) in a human colorectal carcinoma cell line Biochem Pharmacol 1 667–76 Occurrence Handle10.1016/S0006-2952(97)00541-8

    Article  Google Scholar 

  20. M Kusunoki H Yanagi H Kotera M Noda T Yamamura (1998) ArticleTitleEffects of pharmacokinetic modulating chemotherapy using oral UFT and continuous venous 5FU infusion on the prognosis of irradiated rectal carcinomas with p53 overexpression Int J Oncol 13 653–7 Occurrence Handle9735391 Occurrence Handle1:CAS:528:DyaK1cXmsVCltbk%3D

    PubMed  CAS  Google Scholar 

  21. M Kusunoki H Yanagi M Noda T Yamamura (1998) ArticleTitleThe usefulness of pharmacokinetic modulating chemotherapy (UFT plus 5FU) in the treatment of unresectable colorectal carcinomas Oncol Rep 6 547–52

    Google Scholar 

  22. M Kusunoki H Yanagi M Noda R Yoshikawa T Yamamura (2000) ArticleTitleResults of pharmacokinetic modulating chemotherapy in combination with hepatic arterial 5-fluorouracil infusion and oral UFT after resection of hepatic colorectal metastases Cancer 15 1228–35 Occurrence Handle10.1002/1097-0142(20000915)89:6<1228::AID-CNCR6>3.0.CO;2-O

    Article  Google Scholar 

  23. R Yoshikawa M Kusunoki H Yanagi M Noda JI Furuyama T Yamamura et al. (2001) ArticleTitleDual antitumor effects of 5-fluorouracil on the cell cycle in colorectal carcinoma cells: a novel target mechanism concept for pharmacokinetic modulating chemotherapy Cancer Res 1 1029–37

    Google Scholar 

  24. Y Inoue C Miki J Hiro E Ojima K Yamakado K Takeda et al. (2005) ArticleTitleImproved survival using multi-modality therapy in patients with lung metastases from colorectal cancer: a preliminary study Oncol Rep 14 1571–6 Occurrence Handle16273258

    PubMed  Google Scholar 

  25. R Humerickhouse K Lohrbach L Li WF Bosron ME Dolan (2000) ArticleTitleCharacterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2 Cancer Res 1 1189–92

    Google Scholar 

  26. G Xu W Zhang MK Ma HL McLeod (2002) ArticleTitleHuman carboxylesterase 2 is commonly expressed in tumor tissue and is correlated with activation of irinotecan Clin Cancer Res 8 2605–11 Occurrence Handle12171891 Occurrence Handle1:CAS:528:DC%2BD38XmvVahsL0%3D

    PubMed  CAS  Google Scholar 

  27. SB Liggett (2001) ArticleTitlePharmacogenetic applications of the Human Genome Project Nat Med 7 281–3 Occurrence Handle11231618 Occurrence Handle10.1038/85411 Occurrence Handle1:CAS:528:DC%2BD3MXhvVOlu7s%3D

    Article  PubMed  CAS  Google Scholar 

  28. LB Saltz J Kanowitz NE Kemeny L Schaaf D Spriggs BA Staton et al. (1996) ArticleTitlePhase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors J Clin Oncol 14 2959–67 Occurrence Handle8918493 Occurrence Handle1:CAS:528:DyaK2sXhtFan

    PubMed  CAS  Google Scholar 

  29. A Falcone A Di Paolo G Masi G Allegrini R Danesi M Lencioni et al. (2001) ArticleTitleSequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients J Clin Oncol 19 3456–62 Occurrence Handle11481350 Occurrence Handle1:CAS:528:DC%2BD3MXmtlGhurs%3D

    PubMed  CAS  Google Scholar 

  30. RH Mathijssen S Marsh MO Karlsson R Xie SD Baker J Verweij et al. (2003) ArticleTitleIrinotecan pathway genotype analysis to predict pharmacokinetics Clin Cancer Res 15 3246–53

    Google Scholar 

  31. ER Fearon B Vogelstein (1990) ArticleTitleA genetic model for colorectal tumorigenesis Cell 1 759–67 Occurrence Handle10.1016/0092-8674(90)90186-I

    Article  Google Scholar 

  32. Y Tsujimoto N Ikegaki CM Croce (1987) ArticleTitleCharacterization of the protein product of bcl-2, the gene involved in human follicular lymphoma Oncogene 2 3–7 Occurrence Handle3325884 Occurrence Handle1:CAS:528:DyaL1cXptVSrsQ%3D%3D

    PubMed  CAS  Google Scholar 

  33. JC Reed (1994) ArticleTitleBcl-2 and the regulation of programmed cell death J Cell Biol 124 1–6 Occurrence Handle8294493 Occurrence Handle10.1083/jcb.124.1.1 Occurrence Handle1:CAS:528:DyaK2cXntl2mtA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  34. T Ohmori ER Podack K Nishio M Takahashi Y Miyahara Y Takeda et al. (1993) ArticleTitleApoptosis of lung cancer cells caused by some anti-cancer agents (MMC, CPT-11, ADM) is inhibited by bcl-2 Biochem Biophys Res Commun 15 30–6 Occurrence Handle10.1006/bbrc.1993.1377

    Article  Google Scholar 

  35. MI Walton D Whysong PM O'Connor D Hockenbery SJ Korsmeyer KW Kohn (1993) ArticleTitleConstitutive expression of human Bcl-2 modulates nitrogen mustard and camptothecin induced apoptosis Cancer Res 15 1853–61

    Google Scholar 

  36. F Di Nicolantonio SJ Mercer LA Knight FG Gabriel PA Whitehouse S Sharma et al. (2005) ArticleTitleCancer cell adaptation to chemotherapy BMC Cancer 18 78 Occurrence Handle10.1186/1471-2407-5-78 Occurrence Handle1:CAS:528:DC%2BD2MXpsFGqsrw%3D

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, 514-8507, Japan

    Yasuhiro Inoue, Chikao Miki, Hideki Watanabe, Junichiro Hiro, Yuji Toiyama, Eiki Ojima & Masato Kusunoki

  2. Second Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan

    Hidenori Yanagi

Authors
  1. Yasuhiro Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chikao Miki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hideki Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Junichiro Hiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuji Toiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eiki Ojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hidenori Yanagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masato Kusunoki
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Inoue, Y., Miki, C., Watanabe, H. et al. Schedule-dependent cytotoxicity of 5-fluorouracil and irinotecan in a colon cancer cell line. J Gastroenterol 41, 1149–1157 (2006). https://doi.org/10.1007/s00535-006-1904-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-006-1904-0

Key words

Search

Navigation