Cited 0 times in

86 0

인체 폐암세포주에서 Buthionine Sulfoximine 투여가 Cisplatin 및 Adriamycin의 세포독성도에 미치는 영향

Other Titles
 Modulation of cisplatin and adriamycin cytotoxity with buthionine sulfoximine in human lung cancer cell lines 
Authors
 천선희 
Issue Date
1993
Description
의학과/박사
Abstract
[한글] 폐암환자에서 항암제에 대한 약제내성은 치료실패의 주요한 원인이며, 암세포가 약제내성을 획득하는 방법은 복합적으로 띠에 대한 많은 기전들이 보고되고 있다. 최근 cisplatin, adria-mycin 및 alkyl화 약물 같은 항암제의 내성 발현에 세포내 glutathione 증가가 큰 역할을 한다고 한다. Buthionine sulfoximine은 glutathione 합성효소 억제제로 glutathione 함량을 감소시켜 세포의 방사선 감수성을 증가시키고 cisplatin이나 adriamycin에 대해 내성을 지닌 사람이나 쥐의 난소암 및 유방암 세포주의 약제 감수성을 증가시킴 이 보고되고 있다. Gluta-thione은 거의 모든 포유동물 세포내에 존재하는 nonprotein thiol로서 세포막 안정, 아미노산 이동, 효소 활성화에 중요하다. 또한 glutathione은 체내에서 생성된 radical이나 각종 외인성약물(xenobiotics)로 부터 형성된 반응물질을 해독 시켜 세포를 보호하며 항암제의 작용을 조정하는 데에도 큰 역할을 한다. 따라서 본 연구에서는 폐암세포주에서 세포내 glutathione 함량과 cisplatin 및 adriamycin의 세포독성도와의 관계를 조사하고, buthionine sulfoximine투여로 이들 항암제의 세포독성 효과를 증강시킬 수 있는지를 조사하였으며 나아가 이의 임상응용 가능성을 모색하고자 하였다. 실험에 사용한 폐암세포주는 미국 국립암연구소에서 수립된 소세포암세포주인 NCI-H2O9와 비소세포암세포주인 NCI-H727, NCI-H8IO 및 NCI-H1299이었으며, 다약제내성유전자(MDRI)의 표현정도를 slot blot으로 관찰하고,glutathione 합성효소 억제물질인 buthio-nine sulfoxmine을 투여하여 세포내 glutathione 함량 변동에 따른 adriamycin과 cis-platin의 세포독성도 및 약제 상호작용을 조사분석하여 다음과 같은 결과를 얻었다. 1. Adriamycin과 cisplatin에 대한 폐암세포주의 약제내성 정도는 세포내 glutathione 농도보다는 다약제내성유전자의 표현정도가 우선하며, glutathione 함량이 일정농도 이상인 경우에만 cisplatin에 대한 내성에 관여할 것으로 추정되었다. 2. 5-Fluorouracil에 대한 내성은 다약제내성유전자의 표현이나 g1utathione 함량과는 다른 기전에 의할 것으로 추정되었다. 3. 폐암세포주에서 다약제내성유전자 표현이 음성인 경우 buthionine sulfoximine의 투여는 adriamycin과 cisplatin에 대한 약제감수성을 증가시켰으나, 다약제내성유전자 표현이 양성인 경우 adriamycin 또는 cisplatin의 약제내성에 별 영향을 주지 않았다. 이상의 결과로 인체 폐암세포주의 adriamycin 및 cisplatin의 세포독성도를 증가시키기 위하여는 다약제내성유전자 양성 세포주의 경우 p-glycoprotein을 역전시키기 위한 변조물질의 투여가 우선적이겠으나 다약제내성유전자 음성 세포주의 경우 buthionine sulfoximine 투여로 adriamycin 및 cisplatin의 효과를 크게 증가시킬 수 있을 것으로 추정되므로 cisplatin 및 adriamycin을 많이 사용하는 폐암환자의 치료에 상당히 도움이 되리라 생각하며 실제 임상시험을 통하여 그 효과를 검증해 볼 필요가 있을 것으로 생각한다. Modulation of cisplatin and adriamycin cytotoxicity with buthionine sulfoximine in human lung cancer cell linens Seon Hee Cheon Department of Medical Science The Graduate School, Yonsei University (Directed by Professor Sung Kyu Kim) Cisplatin and adriamycin have been proven to be the most effective drugs for lung cancer. However, repeated courses of chemotherapy frequently result in a decreased therapeutic response accompanied by the emergence of an acquired drug-resistance. Recently it has been demonstrated that the resistance to cisplatin, adriamycin or alkylating agents may be due to elevated intracellular glutathione levels in human and rodent tumor cell lines. Depletion of glutathione by buthionine sulfoximine, selective inhibitor of the rate-limiting enzyme in glutathione biosynthesis, has been found to enhance the cytolysis of several tumors and to make tumor cells more suscep-tible to irradiation and certain chemotherapeutic agents. Glutathione is a nonprotein thiol present in most mammalian cells and is important in modulating the action of antitumor agents by direct chemical reaction with either the drug or reactive species. This study was aimed to investigate any relationship between intracellular glutathione levels and sensitivity to cisplatin and adriamycin, and whether cytotoxicity to cisplatin and adriamycin could be increased with buthionine sulfoximine using human lung cancer cell lines such as NCI-H209(small cell carcinoma) and NCI-H727, NCI-H81O and NCI-H1299(non-small cell carcinoma). The MDRI RNA expression in cell lines was investigated by performing RNA slot blot analysis. The intracellular glutathione levels was examined before and after administration of buthionine sulfoximine. Drug sensitivity assays were performed using a modified MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl -1-butene) method. The following results were drawn; 1. The resistance to adriamycin and cisplatin in human lung cancer cell lines was closely related to multi-drug resistance expression level rather than intracellular glutathione level. Cisplatin resistance seemed to be related to the glutathione level above some concentrations. 2. 5-Fluorouracil resistance seemed not to be related to multi-drug resistance expression or flu-tathione level. 3. Buthionine sulfoximine was not effective on adriamycin and cisplatin cytotoxicity in MDRI positive cells, but effective in MDRI negative cells. It is suggested that buthionine sulfoximine is effective supplement to adriamycin and cisplatin in MDRI negative cells. And its effectiveness in human lung cancer patients needs a further clinical studies.
[영문] Cisplatin and adriamycin have been proven to be the most effective drugs for lung cancer. However, repeated courses of chemotherapy frequently result in a decreased therapeutic response accompanied by the emergence of an acquired drug-resistance. Recently it has been demonstrated that the resistance to cisplatin, adriamycin or alkylating agents may be due to elevated intracellular glutathione levels in human and rodent tumor cell lines. Depletion of glutathione by buthionine sulfoximine, selective inhibitor of the rate-limiting enzyme in glutathione biosynthesis, has been found to enhance the cytolysis of several tumors and to make tumor cells more suscep-tible to irradiation and certain chemotherapeutic agents. Glutathione is a nonprotein thiol present in most mammalian cells and is important in modulating the action of antitumor agents by direct chemical reaction with either the drug or reactive species. This study was aimed to investigate any relationship between intracellular glutathione levels and sensitivity to cisplatin and adriamycin, and whether cytotoxicity to cisplatin and adriamycin could be increased with buthionine sulfoximine using human lung cancer cell lines such as NCI-H209(small cell carcinoma) and NCI-H727, NCI-H81O and NCI-H1299(non-small cell carcinoma). The MDRI RNA expression in cell lines was investigated by performing RNA slot blot analysis. The intracellular glutathione levels was examined before and after administration of buthionine sulfoximine. Drug sensitivity assays were performed using a modified MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl -1-butene) method. The following results were drawn; 1. The resistance to adriamycin and cisplatin in human lung cancer cell lines was closely related to multi-drug resistance expression level rather than intracellular glutathione level. Cisplatin resistance seemed to be related to the glutathione level above some concentrations. 2. 5-Fluorouracil resistance seemed not to be related to multi-drug resistance expression or flu-tathione level. 3. Buthionine sulfoximine was not effective on adriamycin and cisplatin cytotoxicity in MDRI positive cells, but effective in MDRI negative cells. It is suggested that buthionine sulfoximine is effective supplement to adriamycin and cisplatin in MDRI negative cells. And its effectiveness in human lung cancer patients needs a further clinical studies.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/117127
Appears in Collections:
2. 학위논문 > 1. College of Medicine (의과대학) > 박사
사서에게 알리기
  feedback
Fulltext
교내이용자 서비스로 제공됩니다.
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse