Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Synergism Induced by Combination of Farnesyl Transferase Inhibitor SCH66336 and Insulin like-Growth Factor Binding Protein-3 in apoptosis of Non-Small Cell Lung Cancer Cell lines

비소세포성 폐암 세포주에서 Farnesyl Transferase Inhibitor SCH66336과 인슐린양 성장 인자 결합 단백-3의 병용처리에 의한 세포고사 상승 작용

  • Kim, Young (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kim, Se Kyu (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kim, Hyung Jung (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Chang, Joon (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Ahn, Chul Min (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Kim, Sung Kyu (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Chang, Yoon Soo (Department of Internal Medicine, Yonsei University College of Medicine)
  • 김영 (연세대학교 의과대학 내과학교실) ;
  • 김세규 (연세대학교 의과대학 내과학교실) ;
  • 김형중 (연세대학교 의과대학 내과학교실) ;
  • 장준 (연세대학교 의과대학 내과학교실) ;
  • 안철민 (연세대학교 의과대학 내과학교실) ;
  • 김성규 (연세대학교 의과대학 내과학교실) ;
  • 장윤수 (연세대학교 의과대학 내과학교실)
  • Received : 2004.11.05
  • Accepted : 2004.12.22
  • Published : 2005.02.28
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Abstract

Background : Insulin-like growth factor binding protein (IGFBP)-3 regulates non-small cell lung cancer(NSCLC) cell proliferation in vitro and in vivo by inhibiting IGF-mediated signaling pathways. To have better strategies for the treatment of lung cancer, we analyzed the combining effects of adenovirus expressing IGFBP-3 (Ad5CMV-BP3) and SCH66336, a farnesyl transferase inhibitor (FTI) designed to block Ras-mediated proliferative signaling pathways. Methods : To measure the combining effects of Ad5CMV-BP3 and SCH66336 on the proliferation of NSCLC cells, human NSCLC cell lines (H1299, H596, A549, H460, and H358), SCH66336, recombinant adenovirus expressing IGFBP-3 (Ad5CMV-BP3) and athymic nude mice were used in these experiments. Results : The combination of Ad5CMV-BP3 and SCH66336 produced a synergistic enhancement in antiproliferative effects over a range of clinically achievable concentrations in a variety of NSCLC cell lines. Furthermore, we observed a significant reduction in growth of NSCLC xenograft induced in athymic nude mice. Conclusion : In conclusion, this study demonstrated for the first time that the FTI SCH66336 synergizes with IGFBP-3 and enhances its apoptotic activity in NSCLC cells in vitro and in vivo. The combined treatment of Ad5CMV-BP3 and SCH66336 raises the possibility of using this regimen in clinic for the treatment of NSCLC.

연구배경 : 인슐린 양 성장 인자 결합 단백질-3 (IGF binding protein-3, IGFBP-3)는 생체내와 실험관내에서 인슐린 양 성장인자 매개 신호전달 체계를 억제하여 비소 세포성 폐암 세포의 증식을 조절하는 것으로 알려져 있다. 이에 본 연구에서는 비소세포성 폐암의 치료에 있어 IGFBP-3를 이용한 치료전략의 개발을 위하여 IGFBP-3(Ad5CMV-BP3)와 FTI SCH66336의 병용치료 상승작용을 분석하였다. 방 법 : 비소세포성 폐암 세포주의 성장에 Ad5CMV-BP3와 SCH66336의 병용투여가 미치는 효과를 측정하기 위하여 비소세포성 폐암 세포주와 IGFBP-3를 발현하는 recombinant adenovirus(Ad5CMV-BP3)를 이용하였고 흉선이 없는 nude mice의 등에 H1299 폐암 세포를 피하 주사한 후 Ad5CMV-BP3와 SCH66336의 병용치료 상승작용을 단일 치료와 비교 분석하였다. 결 과 : SCH66336과 Ad5CMV-BP3 병용처리는 단일 약제보다 더 큰 증식 억제효과 상승작용을 보였으며 nude mice에서도 병용치료 시 종양의 부피는 매우 의미 있는 감소를 보였다. 결 론 : 본 연구의 결과를 통하여 저자들은 SCH66336이 IGFBP-3와 병용투여시 실험실내와 생체내에서 비소 세포성 폐암세포의 세포자멸사에 상승적인 효과가 있다는 것을 처음으로 입증하였으며, 이는 비소세포성 폐암의 치료에 있어 Ad5CMV-BP3와 SCH66336의 병용치료가 임상적으로 사용될 수 있음을 시사하는 것이라 하겠다.

Keywords

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