Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
권호 표지

The Relationship between Heme Oxygenase-1 Expression and Response to Cisplatin Containing Chemotherapy in Advanced Non-Small Cell Lung Cancer

진행성 비소세포폐암에서 Heme oxygenase-1 발현과 Cisplatin을 포함하는 항암화학요법의 치료반응과의 연관성

  • Yang, Doo Kyung (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Roh, Mee Sook (Department of Pathology, Dong-A University College of Medicine) ;
  • Lee, Kyung Eun (Medical Research Center for Cancer Molecular Therapy, Dong-A University College of Medicine) ;
  • Kim, Ki Nam (Department of Radiology, Dong-A University College of Medicine) ;
  • Lee, Ki Nam (Department of Radiology, Dong-A University College of Medicine) ;
  • Choi, Pil Jo (Department of Thoracic and Cardiovascular Surgery, Dong-A University College of Medicine) ;
  • Bang, Jung Hee (Department of Thoracic and Cardiovascular Surgery, Dong-A University College of Medicine) ;
  • Kim, Bo Kyung (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Seo, Hyo Rim (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Kim, Min Ji (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Kim, Seul Ki (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Lee, Soo-Keol (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Son, Choon Hee (Department of Internal Medicine, Dong-A University College of Medicine)
  • 양두경 (동아대학교 의과대학 내과학교실) ;
  • 노미숙 (동아대학교 의과대학 병리학교실) ;
  • 이경은 (동아대학교 의과대학 암분자치료연구센터) ;
  • 김기남 (동아대학교 의과대학 진단영상의학과교실) ;
  • 이기남 (동아대학교 의과대학 진단영상의학과교실) ;
  • 최필조 (동아대학교 의과대학 흉부외과학교실) ;
  • 방정희 (동아대학교 의과대학 흉부외과학교실) ;
  • 김보경 (동아대학교 의과대학 내과학교실) ;
  • 서효림 (동아대학교 의과대학 내과학교실) ;
  • 김민지 (동아대학교 의과대학 내과학교실) ;
  • 김슬기 (동아대학교 의과대학 내과학교실) ;
  • 이수걸 (동아대학교 의과대학 내과학교실) ;
  • 손춘희 (동아대학교 의과대학 내과학교실)
  • Received : 2005.12.26
  • Accepted : 2006.03.14
  • Published : 2006.03.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background : The overall response (20-30%) to chemotherapy in non-small cell lung cancer (NSCLC) is quite poor. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme degradation. There is increasing evidence suggesting that the induction of HO-1 might have an important protective effect against oxidative stress including cisplatin containing chemotherapy. This study retrospectively investigated the relationship between HO-1 expression and the response to chemotherapy containing cisplatinin advanced NSCLC patients. Material and Methods : The medical records including the responses to chemotherapy of fifty nine cases were evaluated retrospectively, and the tissue samples of these patients were immunohistochemically stained for HO-1. Results : Forty three of the fifty nine patients(72.8%) showed positive staining for HO-1 in their cancer tissues. There was no significant difference according to the cell type, stage and tumor size. In addition, there was no correlation between HO-1 expression and the responses to chemotherapy. Conclusion : HO-1 expression in tumor tissue dose not predict the response to cisplatin containing chemotherapy in advanced NSCLC. Further prospective studies with a larger number of patients will be needed to confirm these results.

연구배경: 항암화학요법은 수술이 불가능한 진행성 비소세포폐암환자에서 주요한 치료 방법이지만 전신 부작용 때문에 모든 환자들에게 권할 수 있는 치료법이 되지 못한다. 만약 항암화학요법에 대한 반응 정도를 예측할 수 있다면 치료계획 수립에 도움이 될 수 있을 것이다. Heme oxygenase(HO)는 헴을 산화 분해하는 효소로 세포를 보호하고 세포자멸사를 억제하는 작용이 있음이 알려져 있다. 이에 저자들은 조직 내 HO-1의 발현이 증가되어 있는 경우는 cisplatin을 포함하는 항암화학요법에 저항성을 보일 것으로 가정하였고, 비소세포폐암조직에서 면역조직화학 염색을 이용하여 HO-1의 발현여부를 평가하고 항암화학요법에 대한 치료반응과의 연관성을 알아보고자 하였다. 방 법: 1997년 7월에서 2004년 7월까지 동아대학병원에 내원하여 진행성 비소세포폐암으로 진단받은 환자 중 cisplatin을 포함한 항암화학요법을 2회 이상 시행 받고 치료에 대한 반응을 평가할 수 있는 59명의 환자를 대상으로 후향적 연구를 시행하였다. 대상 환자들을 cisplatin을 포함하는 항암화학요법에 대한 치료 반응 정도 및 다른 임상 특성에 따라 분류하여 조직 내 HO-1의 발현 정도와의 연관성을 알아보았다. 결 과: 총 59명의 폐암조직에서 HO-1의 발현을 조사한 결과 43명(72.8%)에서 양성을 보였다. 조직형, 병기, 종양의 크기와 HO-1 발현은 통계적으로 유의한 연관성이 없었으며, HO-1의 치료 전 발현도 cisplatin을 포함하는 항암화학요법에 대한 치료효과와의 연관성도 없었다. 결 론: 결론적으로 본 연구에서는 진행성비소세포폐암환자의 치료 전 폐암조직에서 HO-1의 발현여부가 cisplatin을 근간으로 하는 항암화학치료의 반응을 예측하는 인자로서의 통계학적 의미는 찾을 수 없었으며 이를 검정하기위한 전향적 연구가 필요하리라 생각된다.

Keywords

References

  1. Korea National Statistical Office. Deaths and death rate by cause. 2004
  2. Minna JD. Neoplasms of the lung. Harrison's principles of internal medicine. 16th ed. New York: McGraw-Hill; 2005. p. 506-15
  3. Scientific Committee of Korean Academy of Tuberculosis and Respiratory Diseases. The national survey of lung cancer in Korea. Tuberc Respir Dis 1999;46:455-65 https://doi.org/10.4046/trd.1999.46.4.455
  4. Graziano SL. Non-small cell lung cancer: clinical value of new biological predictors. Lung cancer 1997;17:S37-58 https://doi.org/10.1016/S0169-5002(97)00639-9
  5. Fang J, Akaike T, Maeda H. Antiapoptotic role of heme oxygenase(HO) and the potential of HO as a target in anticancer treatment. Apoptosis 2004;9:27-35 https://doi.org/10.1023/B:APPT.0000012119.83734.4e
  6. Liu ZM, Chen GG, Ng EK, Leung WK, Sung JJ, Chung SS. Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells. Oncogene 2004;23:503-13 https://doi.org/10.1038/sj.onc.1207173
  7. Agarwal A, Balla J, Alam J, Croatt AJ, Nath KA. Induction of heme oxygenase in toxic renal injury: a protective role in cisplatin nephrotoxicity in the rat. Kidney Int 1995:48:1298-307 https://doi.org/10.1038/ki.1995.414
  8. Fang J, Sawa T, Akaike T, Greish K, Maeda H. Enhancement of chemotherapeutic response of tumor cells by a heme oxygenase inhibitor, pegylated zinc protoporphyrin. Int J Cancer 2004;109:1-8 https://doi.org/10.1002/ijc.11644
  9. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710-7 https://doi.org/10.1378/chest.111.6.1710
  10. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47:207-14 https://doi.org/10.1002/1097-0142(19810101)47:1<207::AID-CNCR2820470134>3.0.CO;2-6
  11. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A 1968;61:748-55 https://doi.org/10.1073/pnas.61.2.748
  12. Alam J. Heme oxygenase-1: past, present, and future. Antioxid Redox Signal 2002;4:559-62 https://doi.org/10.1089/15230860260220049
  13. Stocker R, MacDonagh AF, Glazer AN, Ames BN. Antioxidant activities of bile pigments: biliverdin and bilirubin. Methods Enzymol 1990;186:301-9 https://doi.org/10.1016/0076-6879(90)86123-D
  14. Verma A, Hirsch DJ, Glatt CE, Ronnett GV, Snyder SH. Carbon monoxide: a putative neural messenger. Science 1993;259:381-4 https://doi.org/10.1126/science.7678352
  15. Applegate LA, Luscher P, Tyrrell RM. Induction of heme oxygenase: a general response to oxidant stress in cultured mammalian cells. Cancer Res 1991;51:974-8
  16. Nath KA, Balla G, Vercellotii GM, Balla J, Jacob HS, Levitt MD, et al. Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest 1992;90:267-70 https://doi.org/10.1172/JCI115847
  17. Tanaka S, Akaike T, Fang J, Beppu T, Ogawa M, Tamura F, et al. Antiapoptotic effect of haem oxygenase-1 induced by nitric oxide in experimental solid tumour. Br J Cancer 2003;88:902-9 https://doi.org/10.1038/sj.bjc.6600830
  18. Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, Beppu T, et al. Induction of heam oxygenase-1 by nitric oxide and ischaemia in experimental solid tumors and implications for tumour growth. Br J Cancer 1999:80:1945-54 https://doi.org/10.1038/sj.bjc.6690624
  19. Agarwal A, Balla J, Alam J, Croatt AJ, Nath KA. Induction of heme oxygenase in toxic renal injury: a protective role in cisplatin nephrotoxicity in the rat. Kidney Int 1995;48:1298-307 https://doi.org/10.1038/ki.1995.414
  20. Yokoyama S, Mita S, Okabe A, Abe M, Ogawa M. Prediction of radiosensitivity in human esophageal squamous cell carcinomas with heme oxygenase-1: a clinicopathologic and immunohistochemical study. Oncol Rep 2001;8:355-8
  21. Yanagawa T, Omura K, Harada H, Nakaso K, Iwasa S, Koyama Y, et al. Heme oxygenase-1 expression predicts cervical lymph node metastasis of tongue squamous cell carcinoma. Oral Oncol 2004;40:21-7 https://doi.org/10.1016/S1368-8375(03)00128-3