Skip to main content

Advertisement

SpringerLink
Log in

Antitumor Effect of Gemcitabine on Orthotopically Inoculated Human Gallbladder Cancer Cells in Nude Mice

  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The prognosis of gallbladder carcinoma is poor; therefore, investigating the efficacy of new chemotherapy agents is essential for the treatments for this tumor. Recently, several studies have reported clinical trials using gemcitabine as treatment for advanced gallbladder cancers. However, the antitumor effects of gemcitabine on gallbladder carcinoma have not been examined in in vitro and in vivo model systems.

Methods

We examined the cytotoxicity of gemcitabine in four biliary tract cancer cell lines using the WST-1 assay. In addition, we examined the effect of gemcitabine on gallbladder cancers resulting from orthotopic inoculation of NOZ gallbladder tumor cells into nude mice. One week after transplantation, the mice were randomized into two groups: In Group A, the mice were treated by an intra-peritoneal injection of 0.9% sodium chloride for three weeks after inoculation (control). In Group B, the mice were treated by an intra-peritoneal injection of gemcitabine (125 mg / kg) for three weeks. All mice were sacrificed one week after the end of treatment, and macroscopic and histological findings were evaluated. The expression levels of proliferating-cell nuclear antigen (PCNA) were examined to investigate cellular proliferation activity, and Tunnel assays were performed to determine apoptotic status. Survival duration of the mice after gemcitabine treatment was compared to that of untreated mice.

Results

The gemcitabine sensitivity of the four biliary tract cancer cell lines was similar in a dose dependent manner. In the in vivo models, the Group A mice showed huge tumors of the gallbladder, with liver invasion and lymph node metastases. However, there were no abdominal tumors in the Group B mice, and microscopic gallbladder cancer could only be detected from histological findings. The mean percent of PCNA-positive tumor cells was significantly higher in tumors from mice in Group A (71.9%) compared to those of Group B (34.7%). The mean percent of Tunnel-positive tumor cells was significantly lower in mice from Group A (2.0%) than those from Group B (5.7%). Survival duration was prolonged significantly in the gemcitabine-treated mice relative to untreated mice.

Conclusions

Gemcitabine treatment may inhibit tumor progression and prolong survival in gallbladder cancer by inhibiting cell proliferation and inducing apoptosis.

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

FIG. 1.
FIG 2.
FIG 3.
FIG 4.
FIG 5.

Similar content being viewed by others

References

  1. Diehl AK. Epidemiology of gallbladder cancer: a synthesis of recent data. J Natl Cancer Inst 1980; 65:1209–14

    PubMed  CAS  Google Scholar 

  2. Gallardo JO, Rubio B, Fodor M, Orlandi L, Yanez M, Gamargo C, Ahumada M. A phase II study of gemcitabine in gallbladder carcinoma. Ann Oncol 2001; 12:1403–6

    Article  PubMed  CAS  Google Scholar 

  3. Tsavaris N, Kosmas C, Gouveris P, et al. Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs 2004; 22:193–8

    Article  PubMed  CAS  Google Scholar 

  4. Eng C, Ramanathan RK, Wong MK, et al. A Phase II trial of fixed dose rate gemcitabine in patients with advanced biliary tree carcinoma. Am J Clin Oncol 2004; 27:565–9

    Article  PubMed  CAS  Google Scholar 

  5. Thongprasert S, Napapan S, Charoentum C, Moonprakan S. Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol 2005; 16:279–81

    Article  PubMed  CAS  Google Scholar 

  6. Gelibter A, Malaguti P, Di Cosimo S, et al. Fixed dose-rate gemcitabine infusion as first-line treatment for advanced-stage carcinoma of the pancreas and biliary tree. Cancer 2005; 104:1237–45

    Article  PubMed  CAS  Google Scholar 

  7. Park JS, Oh SY, Kim SH, Kwon HC, Kim JS, Jin-Kim H, Kim YH. Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study. Jpn J Clin Oncol 2005; 35:68–73

    Article  PubMed  Google Scholar 

  8. Ishii H, Furuse J, Kinoshita T, et al. Treatment cost of pancreatic cancer in Japan: analysis of the difference after the introduction of gemcitabine. Jpn J Clin Oncol 2005; 35:526–30

    Article  PubMed  Google Scholar 

  9. Matsui K, Hirashima T, Nitta T, et al. A phase I/II study comparing regimen schedules of gemcitabine and docetaxel in Japanese patients with stage IIIB/IV non-small cell lung cancer. Jpn J Clin Oncol 2005; 35:181–7

    Article  PubMed  Google Scholar 

  10. Okusaka T, Ishii H, Funakoshi A, et al. Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer. Cancer Chemother Pharmacol 2006; 57:647–53

    Article  PubMed  CAS  Google Scholar 

  11. Bruns CJ, Harbison MT, Davis DW,et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 2000; 6:1936–48

    PubMed  CAS  Google Scholar 

  12. Solorzano CC, Hwang R, Baker CH, et al. Administration of optimal biological dose and schedule of interferon alpha combined with gemcitabine induces apoptosis in tumor-associated endothelial cells and reduces growth of human pancreatic carcinoma implanted orthotopically in nude mice. Clin Cancer Res 2003; 9:1858–67

    PubMed  CAS  Google Scholar 

  13. Horiuchi H, Kawamata H, Fujimori T, Kuroda Y. A MEK inhibitor (U0126) prolongs survival in nude mice bearing human gallbladder cancer cells with K-ras mutation: analysis in a novel orthotopic inoculation model. Int J Oncol 2003; 23:957–63

    PubMed  CAS  Google Scholar 

  14. Horiuchi H, Kawamata H, Furihata T, et al. A MEK inhibitor (U0126) markedly inhibits direct liver invasion of orthotopically inoculated human gallbladder cancer cells in nude mice. J Exp Clin Cancer Res 2004; 23:599–606

    PubMed  CAS  Google Scholar 

  15. Homma S, Hasumura S, Nagamori S, Kameda H. Establishment and characterization of a human gall bladder carcinoma cell line NOZ. Hum Cell 1988; 1:95–7

    PubMed  CAS  Google Scholar 

  16. Habara K, Ajiki T, Kamigaki T, Nakamura T, Kuroda Y. High expression of thymidylate synthase leads to resistance to 5-fluorouracil in biliary tract carcinoma in vitro. Jpn J Cancer Res 2001; 92:1127–32

    PubMed  CAS  Google Scholar 

  17. Knuth A, Gabbert H, Dippold W, et al. Biliary adenocarcinoma characterization of three new human tumor cell lines. J Hepatol 1988; 1:579–96

    Article  Google Scholar 

  18. Ajiki T, Kamigaki T, Hasegawa Y, et al. Proliferating cell nuclear antigen, p53, and c-erbB-2 expression in relation to clinicopathological variables and prognosis in cancer of the ampulla of Vater. Hepatogastroenterology 2001; 48:1266–70

    PubMed  CAS  Google Scholar 

  19. Kakinoki K, Fujino Y, Suzuki Y, et al. Protection against ischemia/reperfusion injury by the cavitary two-layer method in canine small intestinal transplantation with reduction of reactive oxygen species. Surgery 2004; 135:642–8

    Article  PubMed  Google Scholar 

  20. Ajiki T, Hirata K, Okazaki T, et al. Thymidylate synthase and dihydropyrimidine dehydrogenase expressions in gallbladder cancer. Anticancer Res 2006; 26:1391–6

    PubMed  CAS  Google Scholar 

  21. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15:2403–13

    PubMed  CAS  Google Scholar 

  22. Okino H, Maeyama R, Manabe T, Matsuda T, Tanaka M. Trans-tissue, sustained release of gemcitabine from photocured gelatin gel inhibits the growth of heterotopic human pancreatic tumor in nude mice. Clin Cancer Res 2003; 9:5786–93

    PubMed  CAS  Google Scholar 

  23. Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, Grindey GB. Evaluation of the antitumor activity of gemcitabine (2′,2′-difluoro-2′-deoxycytidine). Cancer Res 1990; 50:4417–22

    PubMed  CAS  Google Scholar 

  24. Sebastiani V, Ricci F, Rubio-Viquiera B, et al. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: Relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res 2006; 12:2492–7

    Article  PubMed  CAS  Google Scholar 

  25. Gilbert JA, Salavaggione OE, Ji Y, et al. Gemcitabine pharmacogenomics: Cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res 2006; 12:1794–803

    Article  PubMed  CAS  Google Scholar 

  26. Neoptolemos JP, Stocken DD, Friess H, et al. European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350:1200–10

    Article  PubMed  CAS  Google Scholar 

  27. Burris H, Storniolo AM. Assessing clinical benefit in the treatment of pancreas cancer: gemcitabine compared to 5-fluorouracil. Eur J Cancer 1997; 33:S18–22

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Kobe University Graduate School of Medical Sciences, Kobe, Japan

    Yoshiyasu Mita MD, Tetsuo Ajiki MD, Takashi Kamigaki MD, Taro Okazaki MD, Hiroshige Hori MD, Hideki Horiuchi MD, Kenro Hirata MD, Tsunenori Fujita MD & Yoshikazu Kuroda MD

  2. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Japan

    Takahiro Fujimori MD

  3. Department of Gastroenterological Surgery, Kobe University Graduate School of Medical Sciences, 7-5-1 Kusunoki-cho, Kobe, Chuo-ku, 650-0017, Japan

    Tetsuo Ajiki MD

Authors
  1. Yoshiyasu Mita MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tetsuo Ajiki MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Kamigaki MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Taro Okazaki MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroshige Hori MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hideki Horiuchi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenro Hirata MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tsunenori Fujita MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takahiro Fujimori MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshikazu Kuroda MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tetsuo Ajiki MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mita, Y., Ajiki, T., Kamigaki, T. et al. Antitumor Effect of Gemcitabine on Orthotopically Inoculated Human Gallbladder Cancer Cells in Nude Mice. Ann Surg Oncol 14, 1374–1380 (2007). https://doi.org/10.1245/s10434-006-9191-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-006-9191-9

Keywords

Search

Navigation