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Sensitivity of Gastric Cancer Cells to Chemotherapy Drugs in Elderly Patients and Its Correlation with Cyclooxygenase-2 Expression

  • Qiu, Zhen-Qin (Unified Supply Center, The 89th Hospital of Chinese People's Liberation Army) ;
  • Qiu, Zhen-Rong (Pharmacy Department, The 89th Hospital of Chinese People's Liberation Army)
  • Published : 2015.04.29

Abstract

Objective: To explore the sensitivity of gastric cancer cells to chemotherapy drugs in elderly patients and its correlation with cyclooxygenase-2 (COX-2) expression in cancer tissue. Materials and Methods: Forty-three elderly patients with gastric cancer (observation group) and 31 young patients with gastrointestinal tumors (control group) who were all diagnosed by pathology and underwent surgery in the 89th Hospital of Chinese People's Liberation Army were selected. Drug sensitivity testing of tumor cells in primary culture was carried out in both groups using a methyl thiazolyl tetrazolium (MTT) method, and the expression of COX-2 and the factors related to multi-drug resistance (MDR) in cancer tissue were assessed by immunohistochemistry. Results: The inhibition rates (IR) of vincristine (VCR), 5-fluorouracil (5-FU), oxaliplatin (L-OHP), mitomycin (MMC) and epirubicin (eADM) on tumor cells in the observation group were dramatically lower than in the control group, with statistical significance (P<0.05 or P<0.01). The positive rates of COX-2, glutathione s-transferase-${\pi}$ (GST-${\pi}$) and P glycoprotein (P-gp) expression in cancer tissue in the observation group were all higher than in control group (P<0.05), while that of DNA topoisomerase $II{\alpha}$ ($TopoII{\alpha}$) expression lower than in the control group (P<0.01). In the observation group, COX-2 expression in cancer tissue had a significantly-positive correlation with GST-${\pi}$ and P-gp (r=0.855, P=0.000; r=0.240, P=0.026), but a negative correlation with $TopoII{\alpha}$ (r=-0.328, P=0.002). In the control group, COX-2 expression in cancer tissue was only correlated with P-gp positively (r=0.320, P=0.011). Bivariate correlation analysis displayed that COX-2 expression in cancer tissue in the observation group had a significantly-negative correlation with the IRs of 5-FU, L-OHP, paclitaxel (PTX) and eADM in tumor cells (r=-0.723, P=0.000; r=-0.570, P=0.000; r=-0.919, P=0.000; r=-0.781, P=0.000), but with hydroxycamptothecine (HCPT), VCR and 5-FU in the control group (r=-0.915, P=0.000; r=-0.890, P=0.000; r=-0.949, P=0.000). Conclusions: Gastric cancer cells in elderly patients feature stronger MDR, which may be related to high COX-2 expression.

Keywords

Gastric cancer;chemotherapy drugs;cyclooxygenase-2;glutathione s-transferase-${\pi}$;P glycoprotein

References

  1. Basaran H, Koca T, Cerkesli AK, et al (2015). Treatment outcomes and survival study of gastric cancer patients: a retrospective analysis in an endemic region. Asian Pac J Cancer Prev, 16, 2055-60. https://doi.org/10.7314/APJCP.2015.16.5.2055
  2. Fagoonee S, Li H, Zhang H, et al (2014). Gastric cancer as a stem-cell disease: data and hypotheses. Panminerva Med, 56, 289-300.
  3. Hua HK, Jin C, Yang LJ, et al (2015). Expression of cyclooxygenase-2 in squamous cell carcinoma and keratoacanthoma and its clinical significance. Cell Biochem Biophys, Epub ahead of print.
  4. He CZ, Zhang KH (2013). Serum protein and genetic tumor markers of gastric carcinoma. Asian Pac J Cancer Prev, 14, 3437-42. https://doi.org/10.7314/APJCP.2013.14.6.3437
  5. Li XF, Liu AY, Li J, et al (2015). Expression of MGMT, hMLH1 and XRCC1 in gastric cancer tissue and their clinical significance. J Int Transl Med, 3, 535-40.
  6. Liu H, Huang P, Xu X, et al (2009). Anticancer effect of celecoxib via COX-2 dependent and independent mechanisms in human gastric cancers cells. Dig Dis Sci, 54, 1418-24. https://doi.org/10.1007/s10620-008-0510-9
  7. Lu JW, Gao CM, Wu JZ, et al (2013). Polymorphism in the methylenetetrahydrofolate reductase and thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced gastric cancer patients. J Int Transl Med, 1, 4-12.
  8. Liu J, Huang XE, Tian GY, et al (2013). Phase II study on safety and efficacy of Yadanzi(R) (Javanica oil emulsion injection) combined with chemotherapy for patients with gastric cancer. Asian Pac J Cancer Prev, 14, 2009-12. https://doi.org/10.7314/APJCP.2013.14.3.2009
  9. Misron NA, Looi LM, Nik Mustapha NR (2015). Cyclooxygenase-2 expression in invasive breast carcinomas of no special type and correlation with pathological profiles suggest a role in tumorigenesis rather than cancer progression. Asian Pac J Cancer Prev, 16, 1553-8. https://doi.org/10.7314/APJCP.2015.16.4.1553
  10. Segawa E, Sakurai K, Kishimoto H, et al (2008). Expression of cyclooxygenase-2 and DNA topoisomerase II alpha in precancerous and cancerous lesions of the oral mucosa. Oral Oncol, 44, 664-71. https://doi.org/10.1016/j.oraloncology.2007.08.014
  11. Shao Y, Sun K, Xu W, et al (2014). Helicobacter pylori infection, gastrin and cyclooxygenase-2 in gastric carcinogenesis. World J Gastroenterol, 20, 12860-73. https://doi.org/10.3748/wjg.v20.i36.12860
  12. Sierra JC, Hobbs S, Chaturvedi R, et al (2013). Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol, 305, G196-203. https://doi.org/10.1152/ajpgi.00495.2012
  13. Sui H, Zhou S, Wang Y, et al (2011). COX-2 contributes to P-glycoprotein-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer. Carcinogenesis, 32, 667-75. https://doi.org/10.1093/carcin/bgr016
  14. Tan BB, Li Y, Han J, et al (2010). Relationship of cyclooxygenase-2 and multidrug resistance associated factors to chemosensitivities ingastrointestinal carcinomas. J Sichuan University (Medical Edition), 41, 128-31.
  15. Tsuruo T, Naito M, Tomida A, et al (2003). Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Cancer Sci, 94, 15-21. https://doi.org/10.1111/j.1349-7006.2003.tb01345.x
  16. Wang Z, Chen JQ, Liu JL (2014). COX-2 inhibitors and gastric cancer. Gastroenterol Res Pract, Epub ahead of print.
  17. Wei GL, Huang XE, Huo JG, et al (2013). Phase II study on pemetrexed-based chemotherapy in treating patients with metastatic gastric cancer not responding to prior palliative chemotherapy. Asian Pac J Cancer Prev, 14, 2703-6. https://doi.org/10.7314/APJCP.2013.14.5.2703
  18. Xu L, Stevens J, Hilton MB, et al (2014). COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models. Sci Transl Med, 6, 242ra84. https://doi.org/10.1126/scitranslmed.3008455
  19. Xu X, Wang L, Xu HQ, et al (2013). Clinical comparison between paclitaxel liposome (Lipusu(R)) and paclitaxel for treatment of patients with metastatic gastric cancer. Asian Pac J Cancer Prev, 14, 2591-4. https://doi.org/10.7314/APJCP.2013.14.4.2591
  20. Zhu FS, Chen XM, Wang YJ, et al (2007). Antitumor effects of specific cyclooxygenase inhibitors combined with chemotherapeutic agents on gastric cancer cells in vitro. Chinese Journal of Oncology, 29, 186-8.
  21. Klepin HD, Balducci L (2009). Acute myelogenous leukemia in older adults. Oncologist, 14, 222-32. https://doi.org/10.1634/theoncologist.2008-0224
  22. Shi H, Lu D, Shu Y, et al (2008). Expression of multidrugresistance-related proteins P-glycoprotein, glutathione-Stransferases, topoisomerase-II and lung resistance protein in primary gastric cardiac adenocarcinoma. Cancer Invest, 26, 344-51. https://doi.org/10.1080/07357900701788072
  23. Zhang Y, Qu X, Hu X, et al (2009). Reversal of P-glycoproteinmediated multi-drug resistance by the E3 ubiquitin ligase Cbl-b in human gastricadenocarcinoma cells. J Pathol, 218, 248-55. https://doi.org/10.1002/path.2533

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