Journal of Veterinary Clinics (한국임상수의학회지)

The Korean Society of Veterinary Clinics (한국임상수의학회)
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Antiangiogenic Effect of $As_4O_6$ on the Angiogenesis Induced by Vascular Endothelial Growth Factor (VEGF) in the Rat Cornea

랫드 각막에서 Vascular Endothelial Growth Factor(VEGF)로 유발시킨 신생혈관에 대한 $As_4O_6$의 혈관신생 억제효과

  • Kwon Do-hyoung (Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University) ;
  • Jang Jae young (Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University) ;
  • Yi Na-young (Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University) ;
  • Jeong Man-bok (Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University) ;
  • Park Shin-ae (Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University) ;
  • Kim Min-su (Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University) ;
  • Nam Tchi-chou (Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University) ;
  • Park Myung-jin (Laboratory of Cell Biology, Department of Neurosurgery, Korea Institute of Radiological and Medical Sciences, Seoul) ;
  • Bae Ill-ju (Laboratory of Chonjisan Institute, Seoul) ;
  • Rhee Chang-hun (Laboratory of Cell Biology, Department of Neurosurgery, Korea Institute of Radiological and Medical Sciences, Seoul) ;
  • Seo Kang-moon (Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University)
  • 권도형 (서울대학교 수의과대학) ;
  • 장재영 (서울대학교 수의과대학) ;
  • 이나영 (서울대학교 수의과대학) ;
  • 정만복 (서울대학교 수의과대학) ;
  • 박신애 (서울대학교 수의과대학) ;
  • 김민수 (서울대학교 수의과대학) ;
  • 남치주 (서울대학교 수의과대학) ;
  • 박명진 (원자력병원, 신경외과, 분자생물학교실) ;
  • 배일주 ((주) 천지산 연구소) ;
  • 이창훈 (원자력병원, 신경외과, 분자생물학교실) ;
  • 서강문 (서울대학교 수의과대학)
  • Published : 2005.03.01
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Abstract

The purpose of this study was to compare the antiangiogenic effects of As₄O/sub 6/ to those of As₂O₃ on the rat corneal micropocket model induced by VEGF. 20 ng VEGF impregnated pellets were used for angiogenic inducer on the rat cornea micropocket assay in this study. After ophthalmoscopic examination, Sprague-Dawley rats with normal cornea were implanted VEGF pellet. Total 60 eyes were used in this study. Control group only received VEGF pellet, As₂O₃ group followed oral administration of As₂O₃ at a dose of 50 mg/kg per day after VEGF pellet implantation and As₄O/sub 6/ group followed oral administration of As₄O/sub 6/ at a dose of 50 mg/kg per day after VEGF pellet implantation were classified. The eyes were examined under a surgical microscope daily on postoperative from day 3 to day 9 after pellet implantation. The number, length, clock hour of vascularization, and area of vessels in As₄O/sub 6/ group were significantly less evident than those of control group and As₂O₃ group (P < 0.05). In conclusion, As₄O/sub 6/ had better antiangiogenic effects on the new vessel induced by VEGF in the rat cornea.

본 연구는 VEGF로 유발된 랫드 각막 미세낭 모델에서 As₄O/sub 6/와 As₂O₃ 혈관신생 억제효과를 비교하기 위해 실시하였다. 20ng VEGF가 함유된 펠렛을 이식하여 혈관신생을 유도하였다. 안과 검사후 정상적인 각막을 가진 Sprague-Dawley 랫드의 안구 60안을 이용하여 각 20안씩 무작위로 선정하여 대조군(비투약군), As₂O₃군(50mg/kg As₂O₃, 경구투여, 1일 1회), 그리고 As₄O/sub 6/군(50mg/kg As₄O/sub 6/, 경구투여, 1일 1회)으로 나누어 실시하였다. 이식이 완료된 후, 신생혈관의 개수, 길이 및 신생혈관의 각도를 미세수술현미경하에서 이식 3일째부터 9일째까지 매일 검사하였다. 신생혈관의 넓이는 신생혈관의 길이와 각도를 수학적인 공식에 적용하여 계산하였다. 실험 기간동안 As₄O/sub 6/군의 신생혈관 개수, 길이, 각도 및 넓이가 대조군과 As₂O₃군에 비하여 유의성 있게 억압되었다. (P<0.05). 이러한 결과 As₄O/sub 6/는 랫드 각막에서 VEGF에 의해 유도된 신생혈관에 As₂O₃보다 더 뛰어난 억제효과를 가지고 있음을 보여주었다.

Keywords

References

  1. Antman K. Introduction : The history of arsenic trioxide in cancer therapy. Oncologist 2001; 6: 1-2
  2. D'Amato R, Loughnan M, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci 1994; 91: 4082-4085
  3. Fokman J, D'Amore P. Blood vessel formation : what is its molecular basis? Cell 1996; 87: 1153-1155 https://doi.org/10.1016/S0092-8674(00)81810-3
  4. Jin YJ, Lien WH, Tsai WC, Yang GW, Li C, Wu LW. Distinct regulation of genes by bFGF and VEGF-A in endothelial cells. Angiogenesis 2001; 4: 313-321 https://doi.org/10.1023/A:1016080321956
  5. Jing Y, Dai J, Chalmers-Redman R. Tatton W, Waxman S. Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood 1999; 94: 2102-2111
  6. Kenyon B, Voest E, Chen C, Flynn E, Fokman J, D'Amato R. A Model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci 1996; 37: 1625-1632
  7. Kenyon B, Browne F, D'Amato R. Effect of thalidomide and related metabolites in a mouse corneal model of neocvascularization. Exp Eye Res 1997; 64: 971-978 https://doi.org/10.1006/exer.1997.0292
  8. Kim K, Li B, Winer J, Armanini M, Gillett N, Phillips H, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362: 841-844 https://doi.org/10.1038/362841a0
  9. Konig A, Wrazel L, Warrell Jr R, Rivi R, Pandolfi P, Jakubowski A, Gabrilove J, Comparative activity of melarsoprol an arsenic trioxide in chronic B-cell leukemia Lines. Blood 1997; 90: 562-570
  10. Lee JB, Jung SE, Lee HC, Kwon HM, Hong BK, Park HY, Kim EK, Oh JH. Effect of vascular endothelial growth factor(VEGF) on the corneal neovascularization and expression of MMP-2,9,TIMP-1,2 and flk-1. J Korean Ophthalmol Soc 2001; 42: 1053-1062
  11. Lew Y, Brown S, Griffin R, Song C, Kim J. Arsenic trioxide causes selective necrosis in solid murine tumors by vascular shutdown. Cancer Res 1999; 59: 6033-6037
  12. Munshi N. Arsenic trioxide : An emerging therapy of multiple myeloma. Oncologist 2001; 6: 17-21
  13. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z, Vascular endothelial growth factor(VEGF) and its receptors. FASEB J 1999; 13: 9-18
  14. Park CH. Angiogenic effect of vascular endothelial growth factor on the rat cornea. Kangwon national univerity. 2003
  15. Park MJ, Park IC, Bae IJ, Seo KM, Lee SH, Hong SI, Eun CK, Zhang W, Rhee CH. Tetraarsenic oxide, a novel orally administrable angiogenesis inhibitor. International Journal of Oncology 2003; 22: 1271-1276
  16. Risau W. Mechanisms of angiogenesis. Nature 1997; 386: 671-674 https://doi.org/10.1038/386671a0
  17. Roboz G, Dias S, Lam G, Lane W, Soignet S, Warrell Jr R, Rafii S. Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood 2000; 96: 1525-1530
  18. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY, Use of arsenic trioxde($As_2O_3$) in the treatment of acute promyelocytic leukemia(APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997; 89: 3354-3360
  19. Soignet S, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti L, Corso D, DeBlasio A, Garbrilove J, Scheinberg D, Pandolfi P, Warrell R. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. NEJM 1998; 339: 1341-1348 https://doi.org/10.1056/NEJM199811053391901
  20. University of Tennessee, Department of EHS. 1997. Arsenic trioxide. http://web.utk.edu/~ehss/arsenic/arsenicb.htm
  21. Waxman S, Anderson K. History of the development of arsenic derivatives in cancer therapy. Oncologist 2001; 6: 3-10
  22. Wilson H. Miller, Jr., Hyman M. Schipper, Janet S. Lee, Jack Singer, and Samuel Waxman. Mechanisms of action of arsenic trioxide. Cancer Research 2002; 62: 3893-3903
  23. Yoo MH, Kim JT, Rhee CH, Park MJ, Bae IJ, Yi NY, Jeong MB, Jeong SM, Nam TC, Seo KM. Reverse effects of tetraarsenic oxide on the angiogenesis induced by nerve growth factor in the rat cornea. J Vet Med Sci 2004; 66: 1091-1095 https://doi.org/10.1292/jvms.66.1091