Journal of Chest Surgery

The Korean Society for Thoracic and Cardiovascular Surgery (대한심장혈관흉부외과학회)
권호 표지

Human Lung Cancer Cell Xenografts Implanted under the Capsule of Kidney, Spleen and Liver

폐암 세포주를 사용한 신, 비장 및 간 피막하 분식법의 비교

  • 김수현 (고신대학교 의학부 흉부외과학교실) ;
  • 김종인 (고신대학교 의학부 흉부외과학교실) ;
  • 이해영 (고신대학교 의학부 흉부외과학교실) ;
  • 조봉균 (고신대학교 의학부 흉부외과학교실) ;
  • 박성달 (고신대학교 의학부 흉부외과학교실) ;
  • 김송명 (고신대학교 의학부 흉부외과학교실)
  • Published : 2003.10.01
Download PDF
⟨ Previous Next ⟩

Abstract

Bakground : Complete resection by the surgery has been selected as the treatment of choice in lung cancer patients, but in cases of recurrence after excision or inoperable cases, the importance of anticancer chemotherapy has been emphasized. If one can select a set of the sensitive chemotherapeutic agents before anticancer chemotherapy, it will give more favourable results. Subrenal capsular assay has been recognized as a useful in-vivo chemosensitivity test of thoracic and abdominal tumors and it can be done in a short time for a rapid interpretation of tumor responsiveness to anticancer chemotherapeutic drugs. It has been reported that various kinds of cancer cells can be implantable to the kidney, but so far there is no comparative study of xenogeneic cell implantation on liver, spleen and kidney. The author implanted the human lung cancer cells under the capsule of S.D rat's liver, spleen and kidney respectively and compared the pattern of growth and histology. Material and Method: After incubation of human lung cancer cell line (SW-900 G IV) in RPMI 1640 (Leibovitz L-15 medium) culture media, 3${\times}$3${\times}$3 mm size fibrin clots which contain 108 cancer cells were made. Thereafter the fibrin clots were implanted at subcapsule area of liver, spleen and kidney of S.D. female rat. For immune suppression, cyclosporin-A (80 mg/Kg) was injected subcutaneously daily from post-implantation first day to sixth day. The body weight was measured at pre and post implantation periods. The growth pattern and the size of tumor mass were observed and the pathologic examination and serum tumor marker tests were performed. Result: Body weight increased in both of control and experimental groups. Serum Cyfra 21-1 was not detected. Serum levels of CEA and NSE revealed no significant change. The SCC-Ag increased significantly in implanted group. The growth rate of human lung cancer cells which was implanted on spleen was higher than on liver or kidney. The surface area, thickness, and volume of tumor mass were predominant at spleen. The success rates of implantation were 80% on kidney, 76.7% on spleen and 43.3% on liver. Pathologic examination of implanted tumors showed characteristic findings according to different organs. Tumors that were implanted on kidney grew in a round shape, small and regular pattern. In the spleen, tumors grew well and microscopic neovascularization and tumor thrombi were also found, but the growth pattern was irregular representing frequent daughter mass. Human lung cancer cells that were implanted in the liver, invaded to the liver parenchyme, and had low success rate of implantation. Microscopically, coagulation necrosis and myxoid fibrous lesion were observed. Conclusion: The success rate of implantation was highest in the kidney. And the mass revealed regular growth that could be measured easily. The SCC-Ag was presented earlier than CEA or Cyfra21-1. The Cyfra21-1 was not detected at early time after implantation. The best model for tumor implantation experiment for chemosensitivity test was subrenal capsular analysis than liver and spleen and the useful serum tumor marker in early period of implantation was the SCC-Ag.

배경: 폐암은 근치적 절제술이 가장 좋은 치료법이나 수술 후에 재발한 경우나 수술 시기가 지난 경우에는 항암 화학요법의 중요성이 강조된다. 항암 치료 전에 감수성 있는 항암 화학 치료제가 선별되어진다면 치료 효과를 극대화할 수 있다. 신피막하 분석법은 흉, 복부 종양의 생체 내 검사법으로 중요성이 인정되고 있고 항암 감수성 검사로서도 짧은 기간 내에 판별이 가능한 이점이 있다. 신장은 각종 암세포의 이식 장소로 잘 알려져 있으나 비장이나 간에서의 이식 성적을 비교한 연구는 없는 실정이다. 인체 암세포 이식의 실험방법 중에 비장과 간장에 암 세포주를 이식하였을 경우와 신장에 시행되는 신피막하 분석법에 의한 성장의 차이점 유무를 평가하였다. 대상 및 방법: 인체 폐암 세포주(SW-900 G IV)를 RPMI 1640 (Leibovitz L-15 medium)배지에서 배양하여 fibrin clot으로 만들어 $10^{8}$ 개의 암세포가 포함되도록 한 후 3${\times}$${\times}$3mm의 크기로 Spague Dawely (S.D.) 암컷 쥐의 신, 비장 및 간 피막하에 이식하였다. 이식 후 1일부터 6일간 면역억제를 위하여 cyclosporin-A (80 mg/kg)를 피하투여하였다. 이식 전후 실험동물의 체중 변화, 종양의 성장 여부 및 종양의 크기를 계측하고 병리 조직 검사와 혈청 내 암 표지자 검사를 실시하여 비교하였다. 걸과: 실험 5.D. 쥐의 체중 변화는 대조군이나 실험 군 모두에서 체중 증가가 있었다. 혈청 내 암 표지자의 정량 검사 결과 Cyfra 21-1은 검출되지 않았고, CEA및 NSE는 의미 있는 변화가 없었으며, SCC-Ag이 실험 군에서 유의한 증가가 있었다. 비장에 이식한 폐암 세포주의 성장이 신장 및 간장에 비해 더 증가된 결과를 보였다. 표면적, 두께와 용적 모두가 비장에서 유의한 증가를 나타내었다. 이식 성공률은 신장이 80%, 비장이 76.7%, 간장이 43.3%이었다. 병리학적 검사 결과 신장에는 비교적 둥글게 성장하며 크기는 제일 작았으며 성장 방향이 일정한 모양을 보이는 특징이 있으며 비장은 성장이 잘되어 제일 큰 종양을 형성하나 불규칙한 성장과 위성 종양(satellite tumor)이 빈번히 발견되었으며 현미경적으로는 혈관 신생과 함께 종양 혈전이 발견되었다. 간장은 간 내부로 침투 성장하여 이식 성공률이 가장 저조하며 현미경적 소견은 응고성 괴사와 점액양 섬유성 병변을 가지는 특징을 보였다. 걸론: 이식 성공률은 신장과 비장이 높으나, 성장이 일정하고 계측이 용이한 것은 신장이었다. 혈청 암 표지자는 SCC-Ag이 가장 조기에 반응하였으며, Cyfra 21-1은 조기에 검출되지 않았다. 이상에서 감수성 검사를 위한 종양이식 실험에 이용하기에 가장 적합한 장기는 신장을 이용한 신피막하 이식법으로 생각되며, 조기에 유용한 암표지자 검사는 SCC-Ag 정량법이라고 판단된다.

Keywords

References

  1. Cancer Letters v.162 no.2 Susceptibility of lean and obese Zucker rats to tumorigenesis induced by N-methyl-N-nitrosourea Lee,W.M.;Lu,S.;Medline,A.;Archer,M.C. https://doi.org/10.1016/S0304-3835(00)00635-2
  2. Cancer Res v.38 no.1 Effect of serial passage in nude athymic mice on the growth characteristics and chemotherapy responsiveness of 13762 and R3230AC mammary tumor xenografts Bogden,A.E.;Kelton,D.E.;Cobb,W.R;Gulkin,T.A.;Johnson,R.K.
  3. Exp Cell Biol v.47 no.4 Growth of human tumor xenografts implanted under the renal capsule of normal imunocompetent mice Bogden,A.E.;Haskell,P.m.;LePage,D.J.;Keltom,D.E.;Cobb,W.R.;Esber,H.J.
  4. Eur J Cancer Clin Oncol v.19 no.7 Comparison between macroscopic and microscopic evaluation of tumour responsiveness using the subrenal capsule assay Edelstein,M.B.;Fiebig,H.H.;Smink,T.;Van Putten,L.M.;Schuchhardt,C. https://doi.org/10.1016/0277-5379(83)90070-6
  5. Proc Natl Acad Sci U.S.A. v.81 no.24 Transplantation of human or rodent tumors into cyclosporine-treated mice: a feasible model for studies of tumor biology and chemotherapy Fingert,H.J.;Treiman,A.;Pardee,A.B. https://doi.org/10.1073/pnas.81.24.7927
  6. Cancer Res v.47 no.14 Rapid growth of human cancer cells in a mouse model with fibrin clot subrenal capsule assay Fingert,H.J.;Chen,Z.;Mizrahi,N.;Gajewski,W.H.;Bamberg,M.P.;Kradin,R.L.
  7. Proc. Symp. on the use of Athymic (Nude) Mice in cancer Research A rapid screening method for testing chemotherapentic agents human tumor xenografts Bogden,A.E.;Kelton,D.F.;Cobb,W.R.;Esber,H.J.;Houchons,D.P.;Drejera,A.A.(eds.)
  8. Expl Cell Biol v.47 Growth of human tumor venografts implanted under the renal capsule of normal immunocompetent mice Bogden,A.E.;Haskell,P.M.;Lepage,D.J.;KeHon,D.E.;Cobb,W.R.;Esber,H.J.
  9. Gynecol Oncol v.17 Chemosensitivity testing of nonsolid tumors by the subrenal-capsule implant assay Stratton,J.A.;Micha,J.P.;Rettenmair,M.A.;Braley,P.S.;Disaia,P.J. https://doi.org/10.1016/0090-8258(84)90075-1
  10. Am J Hygiene v.78 The growth and maintenance of tissue-cell cultures in free gas exchange with the atmosphere Leibovitz,A.
  11. Cancer Res v.47 Rapid growth of human cancer cells in a mouse model with fibrin clot subrenal capsule assay Fingert,H.J.;Chen,Z.;Mizrahi,N.;Gajewski,W.H.;Bamberg,M.P.;Kradin,R.L.
  12. Br J Surg v.71 Advanced gastric cancer Experience in Scotland using 5-Fluorouracil, Adriamycin and Mitomycin C Cunningham,D.;Soukop,M.;Mcardle,C.S.(et al.) https://doi.org/10.1002/bjs.1800710909
  13. Korea J Gen Surg v.39 Subrenal capsule assay (SRCA) for chemosensitivity of anti-cancer drugs with human gastric cancer cell line Lee,M.H.;Back,S.U.;Kim,J.J.;Hur,K.B.
  14. Neurosurgery v.34 no.5 AGM-1470 inhibits the growth of human glioblastoma cells in vitro and in vivo Takamiya,Y.;Brem,H.;Ojeifo,J.;Mineta,T.;Martuza,R.L. https://doi.org/10.1227/00006123-199405000-00013
  15. Cancer v.65 A randomized trial of two vindesine plus cisplatin-containing regimens with the addition of mitomycin or ifosfamide in patients with advanced non-small cell lung cancer Rosell,R.;Abad-E Steve, A.;Mareno,I. https://doi.org/10.1002/1097-0142(19900415)65:8<1692::AID-CNCR2820650805>3.0.CO;2-X
  16. Clin Lung Cancer Ⅰ no.Suppl Ⅰ Chemotherapy regimens in advanced non-small-cell lung cancer: Implications and future perspectives Belani,C.P.
  17. Astrazeneca completes enrollment in phase III non-small cell lung cancer clinical trial program for iressa$^？$ (ID 1839) Wilmington,D.
  18. Br J Cancer v.42 Effect of cyclosporin a on the growth and spontaneous metastasis of syngeneic animal tumors Eccles,S.A.;Heckford,S.E.;Alexander,P. https://doi.org/10.1038/bjc.1980.224
  19. J Chn Invest v.77 Cyclosporin a reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro Slater,L.M.;Sweet,P.;Stuperky,M.;Gupta,S.
  20. Clin Resp Physiol v.22 Role of biological markers and probes in lung carcinomas Dorreen,M.S.
  21. Kyungpook Univ. Med J v.25 no.3 Serum Carcinoembryonic Antigen in Lung Cancer Patients Kim,S.M.
  22. Korean J Thorac Cardiovasc Surg v.30 The study of cyfra 21-1 and epidermal growth factor receptor levels in cancer tissue of bronchogenic carcinoma patients Kim,T.Y.;Kim,S.M.
  23. Cancer Res v.44 no.6 A four-day subrenal capsule assay for testing the effectiveness of anticancer drugs against human tumors Levi,F.A.;Blum,J.P.;Lemaigre,G.;Bourut,C.;Reinberg,A.;Mathe,G.