Radiation Oncology Journal

The Korean Society for Radiation Oncology (대한방사선종양학회)
권호 표지
DOI QR코드

DOI QR Code

Combination Effect of Nimotuzumab with Radiation in Colorectal Cancer Cells

대장암 세포에서 EGFR 저해제 Nimotuzumab의 방사선 병합 효과

  • Shin, Hye-Kyung (Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences) ;
  • Kim, Mi-Sook (Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences) ;
  • Jeong, Jae-Hoon (Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences)
  • 신혜경 (한국원자력의학원 암연구부) ;
  • 김미숙 (한국원자력의학원 방사선종양학과) ;
  • 정재훈 (한국원자력의학원 암연구부)
  • Received : 2010.06.04
  • Accepted : 2010.08.03
  • Published : 2010.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: To investigate the radiosensitizing effect of the selective epidermal growth factor receptor (EGFR) inhibitor nimotuzumab in human colorectal cancer cell lines. Materials and Methods: Four human colorectal cancer cell lines, HCT-8, LoVo, WiDr, and HCT-116 were treated with nimotuzumab and/or radiation. The effects on cell proliferation, viability, and cell cycle progression were measured by MTT, clonogenic survival assay, flow cytometry, and Western blot. Results: An immunoblot analysis revealed that EGFR phosphorylation was inhibited by nimotuzumab in colorectal cancer cell lines. Under these experimental conditions, pre-treatment with nimotuzumab increased radiosensitivity of colorectal cancer cell lines, except for cell line HCT-116. However, cell proliferation or cell cycle progression was not affected by the addition of nimotuzumab, irrespective of irradiation. Conclusion: Nimotuzumab enhanced the radiosensitivity of colorectal cancer cells in vitro by inhibiting EGFR-mediated cell survival signaling. This study provided a rationale for the clinical application of the selective EGFR inhibitor, nimotuzumab in combination with radiation in colorectal cancer cells.

목 적: 대장암 세포에서 epidermal growth factor receptor (EGFR) 저해제인 nimotuzumab에 의한 방사선 민감도 증진 효과를 살펴보고자 한다. 대상 및 방법: 총 4종류의 인간 유래 대장암 세포주인 HCT-8, LoVo, WiDr, HCT-116를 nimotuzumab과 방사선을 병합 처리한 후 세포증식, 생존율, 세포주기 진행에 미치는 영향을 MTT, clonogenic survival assay, flow cytometry와 western blot을 통해 분석하였다. 결 과: 대장암 세포주에서 nimotuzumab에 의해 EGFR 인산화가 억제됨을 확인하였고 이러한 조건에서 nimotuzumab이 HCT-116을 제외한 나머지 3종류의 대장암 세포주의 방사선 민감도를 증진시킴을 확인하였다. 반면에, nimotuzumab은 방사선 조사와 무관하게 대장암 세포의 증식이나 세포 주기에는 아무런 영향을 미치지 않았다. 결 론: Nimotuzumab은 EGFR에 의한 세포 생존 신호 전달을 억제함으로써 대장암 세포의 방사선에 대한 민감도를 증가시켰다. 본 연구는 대장암의 방사선 치료에 EGFR 특이적 저해제인 nimotuzumab의 임상 적용 근거를 제공하였다.

Keywords

References

  1. Mendelsohn J. The epidermal growth factor receptor as a target for cancer therapy. Endocr Relat Cancer 2001;8:3-9 https://doi.org/10.1677/erc.0.0080003
  2. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990;61:203-212 https://doi.org/10.1016/0092-8674(90)90801-K
  3. Lee JC, Wang ST, Chow NH, Yang HB. Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer 2002;38:1065-1071 https://doi.org/10.1016/S0959-8049(02)00004-7
  4. Weitz J, Koch M, Debus J, Hohler T, Galle PR, Buchler MW. Colorectal cancer. Lancet 2005;365:153-165 https://doi.org/10.1016/S0140-6736(05)17706-X
  5. Dent P, Reardon DB, Park JS, et al. Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell 1999;10:2493-2506 https://doi.org/10.1091/mbc.10.8.2493
  6. Milas L, Mason K, Hunter N, et al. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 2000;6:701-708
  7. Raben D, Helfrich B, Chan DC, et al. The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 2005;11:795-805
  8. Huang SM, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res 2000;6:2166-2174
  9. Harari PM, Huang SM. Head and neck cancer as a clinical model for molecular targeting of therapy: combining EGFR blockade with radiation. Int J Radiat Oncol Biol Phys 2001;49:427-433 https://doi.org/10.1016/S0360-3016(00)01488-7
  10. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-578 https://doi.org/10.1056/NEJMoa053422
  11. Ettinger DS. Clinical implications of EGFR expression in the development and progression of solid tumors: focus on non-small cell lung cancer. Oncologist 2006;11:358-373 https://doi.org/10.1634/theoncologist.11-4-358
  12. Harari PM, Huang S. Radiation combined with EGFR signal inhibitors: head and neck cancer focus. Semin Radiat Oncol 2006;16:38-44 https://doi.org/10.1016/j.semradonc.2005.08.005
  13. Mateo C, Moreno E, Amour K, Lombardero J, Harris W, Perez R. Humanization of a mouse monoclonal antibody that blocks the epidermal growth factor receptor: recovery of antagonistic activity. Immunotechnology 1997;3:71-81 https://doi.org/10.1016/S1380-2933(97)00065-1
  14. Crombet T, Osorio M, Cruz T, et al. Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol 2004;22:1646-1654 https://doi.org/10.1200/JCO.2004.03.089
  15. Ramos TC, Figueredo J, Catala M, et al. Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3: report from a phase I/II trial. Cancer Biol Ther 2006;5:375-379 https://doi.org/10.4161/cbt.5.4.2522
  16. Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol 2007;29:697-735
  17. Crombet-Ramos T, Rak J, Perez R, Viloria-Petit A. Antiproliferative, antiangiogenic and proapoptotic activity of h-R3: a humanized anti-EGFR antibody. Int J Cancer 2002; 101:567-575 https://doi.org/10.1002/ijc.10647
  18. Akashi Y, Okamoto I, Iwasa T, et al. Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status. Br J Cancer 2008;98:749-755 https://doi.org/10.1038/sj.bjc.6604222
  19. Munshi A, Hobbs M, Meyn RE. Clonogenic cell survival assay. Methods Mol Med 2005;110:21-28
  20. Overman MJ, Hoff PM. EGFR-targeted therapies in colorectal cancer. Dis Colon Rectum 2007;50:1259-1270 https://doi.org/10.1007/s10350-007-0228-3
  21. Wong SF. Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther 2005;27:684-694 https://doi.org/10.1016/j.clinthera.2005.06.003
  22. Shin HK, Kim MS, Lee JK, et al. Combination effect of Cetuximab with radiation in colorectal cancer cells. Tumori. Forthcoming
  23. Thomas M. Cetuximab: adverse event profile and recommendations for toxicity management. Clin J Oncol Nurs 2005;9:332-338 https://doi.org/10.1188/05.CJON.332-338
  24. Crombet T, Torres O, Rodriguez V, et al. Phase I clinical evaluation of a neutralizing monoclonal antibody against epidermal growth factor receptor in advanced brain tumor patients: preliminary study. Hybridoma 2001;20:131-136 https://doi.org/10.1089/02724570152057634
  25. Masucci G, Ragnhammar P, Wersall P, Mellstedt H. Granulocyte-monocyte colony-stimulating-factor augments the interleukin-2-induced cytotoxic activity of human lymphocytes in the absence and presence of mouse or chimeric monoclonal antibodies (mAb 17-1A). Cancer Immunol Immunother 1990;31:231-235 https://doi.org/10.1007/BF01789174
  26. Diaz Miqueli A, Rolff J, Lemm M, Fichtner I, Perez R, Montero E. Radiosensitisation of U87MG brain tumours by anti-epidermal growth factor receptor monoclonal antibodies. Br J Cancer 2009;100:950-958 https://doi.org/10.1038/sj.bjc.6604943

Cited by

  1. The Interplay between Radioresistant Caco-2 Cells and the Immune System Increases Epithelial Layer Permeability and Alters Signaling Protein Spectrum vol.8, pp.None, 2010, https://doi.org/10.3389/fimmu.2017.00223