KR970705638A - 내피 세포 특이적이고 세포 사이클-의존성인 활성 화합물을 사용한 종양의 유전적 치료법(Genetic therapy of tumours with an endothelium cell-specific active substance which is dependent on the cell cycle) - Google Patents
내피 세포 특이적이고 세포 사이클-의존성인 활성 화합물을 사용한 종양의 유전적 치료법(Genetic therapy of tumours with an endothelium cell-specific active substance which is dependent on the cell cycle)Info
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Abstract
종양 유전자 치료용 DNA 서열을 기술한다. 이의 필수 성분으로서 DNA 서열은 활성화 인자 서열, 프로모터 모듈 및 활성 물질의 유전자로 구성된다.
활성화 인자 서열은 세포 특이적 방법으로 증식 내피 세포내 또는 이들 내피세포와 인접한 세포내에서 활성화 된다.
상기 활성은 세포 사이클-특이적 방법으로 프로모터 모듈에 의해 조절된다. 활성 물질은 맥관형성 또는 세포 억제 또는 세포 독성 분자의 억제제이다. DNA 서열은 활성화된 내피 세포에 대해 친화성을 소유하는 리간드로 보충되어 바이러스 또는 비바이러스 벡터내로 삽입된다.
Description
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음
Claims (25)
- 활성화 인자 서열, 프로모터 모듈 및 항종양 물질을 암호화하는 DNA 서열로 구성되는 DNA 작제물을 포함하는, 종양 질환의 예방 또는 치료용 활성 화합물.
- 제1항에 있어서, 프로모터 모듈이 성분 CDE0CHR-Inr을 보유하고 위치≤-20 내지 ≥+30의 cdc25C 프로모터 영역의(뉴클레오타이드 서열 GGCTGGCGGAAGGTTTGAATGGTCAACGCCTGCGGCTGTTGATA TTCTTG), 세포 사이클 의존성 성분을 나타내는 CDE의 서열2(뉴클레오타이드 서열 TGGCGG) 세포 사이클 유전자 상동성 영역을 나타내는 CHR의 서열3(뉴클레오타이드 서열 GTTTGAA)및 개시점을 나타내는 Inr(위치+1) 및 개시를 위해 중요한 근접한 서열을 포함하는 활성 화합물.
- 제1항에 있어서, 내피 세포, 또는 증식 내피 세포의 바로 인접한 세포에서 형성된 전사 인자에 의해 조절되는 활성화 인자 서열[프로모터 서열 또는 인핸서(enhancer)서열]을 포함하는 활성 화합물.
- 제3항에 있어서, CMV 프로모터, CMV 인해서 또는 SV40 프로모터; 내피 세포의 글루코즈-1-운반체, 엔도글린, VEGF 수용체 1 또는 1, 수용체 타이로신 키나제틸-1 또는 틸-2, B61 수용체, B61 리간드, 엔도텔린, 특히 엔도텔린 B 또는 엔도텔린 1, 만노즈-6-포스페이트 수용체, IL-1α또는 IL-1β, IL-1 수용체, CVAM-1 또는 폰 빌레브란트 인자에 대한 프로모터 서열; 결합부위가 5'-TTATCT-3'인 GATA-2 와 같은, 우선적으로 또는 선택적으로 내피세포에서 활성을 나타내는 전자 인자의 올리고머화 결합부위로 구성되는 합성 활성화 인자 서열; VEGF에 대한 인핸서 서열 또는 VEGF 유전자를 조절하는 c-SRC 또는 v-SRC에 대한 c-DNA 서열, 또는 c-SRC 또는 c-SRC에 대한 c-DNA 서열; 또는 마우스 포유동물 종양 바이러스의 포로모터 서열 또는 스테로이드 수용체의 프로모터 서열을 포함하는 활성 화합물.
- 제1항 내지 제4항중 어느 한 항에 있어서, 항종양 활성 화합물의 DNA 서열이, 망막아종 단백질; p110 또는 p107 및 p130 단백질; 단백질 p53; 단백질 p21, 단백질 p16 또는 또 다른 사이클린 의존 키나제(cdK) 억제제; GADD45 단백질; bak 단백질; 맥관형성을 억제하는 단백질; 세포억제효과를 나타내는 단백질; 염증을 자극하는 단백질; 또는 세포 억제제의 전구체를 절단함으로써 세포 억제제를 형성시키는 효소를 암호화하는 활성 화합물.
- 제5항에 있어서, 망막아중 단백질(pRb/p110)을, 이의 246, 350, 601, 605, 780, 786, 787, 800 및 804번 위치의 아미노산을 대체시킴으로써, 예를들면, 아미노산 Thr-246, Ser-601, Ser-605, Ser-780, Ser-786, Ser-787 및 Ser-800을 Ala로 대체하고 아미노산 Thr-350을 Arg로 대체시키며 아미노산 Ser-804을 Glu로 대체시킴으로써, 거대 T 항원과의 결합능력의 손상없이 망막아증 단백질이 더 이상 인산화되지 않도록 하거나; 단백질 p107을 pRb/110과 유사한 방법으로 변이시키거나; 또는 단백질 p130을 pRb/110과 유사한 방법으로 변이시킨 활성 화합물.
- 제5항에 있어서, 단백질 p53에 있어서 세린 392를 제거함으로써 이의 C-말단을 절단시킨 활성 화합물.
- 제1항 내지 제4항중 어느 한 항에 있어서, 항종양 물질이 플라즈미노겐 활성인자 억제제1(PAI-1), PAI02, PAI-3, 안지오스타틴, 혈소판 인자 4, TIMP-1, TIMP-2 또는 TIMP-3인 활성 화합물.
- 제1항 내지 제4항중 어느 한 항에 있어서, 항종양 물질이 페르포린, 그란자임, IL-2, IL-4, IL-12, 인터페론(예:IFNα, IFNβ, 또는 IFNr), TNFα 또는 TNFβ, 온코스타틴 M, RANTES, MCAF, IL-8, MIP-1α, MIP-1β, NAP2, IL-3, IL-5, LIF, IL-11 또는 IL-13인 활성 화합물.
- 제9항에 있어서, 항종양 물질이 면역글로불린의 Fc 단편을 포함하는 융합 단백질인 활성 화합물.
- 제1항 내지 제4항중 어느 한 항에 있어서, 항종양 물질이 효소이고 이러한 효소가 단순 포진(herpes simplex)바이러스 티미딘 키나제, 사이토신 데아미나제, 바리셀라 조스터 바이러스 티미딘 키나제, 니트로리덕타제, β-글루쿠로니다제(특히, 사람, 식물 또는 세균 β-글루쿠로니다제), 카복시펩티다제[바람직하게 슈도모나스(Pseudomonas)로부터], 락타마제[바람직하게 바실러스 세레우스(Bacillus seteus)로부터], 피로글루타메이트 아미노펩티다제, D-아미노펩티다제, 옥시다제, 퍼옥시다제, 포스파타제, 하이드록시니트릴 리이제, 프로테아제, 에스터라제 또는 글리코시다제인 활성 화합물.
- 제11항에 있어서, 효소의 DNA 서열을 점변이 (point mutation)시킴으로써 리소좀 저장이 감소되고 세포외 분비가 증진되는 활성 화합물.
- 제11항에 있어서, 효소의 신호 서열을 이종성(heterologous) 신호 서열로 대체함으로써 세포의 분비를 개선시킨 활성 화합물.
- 제1항 내지 제13항중 어느 한 항에 있어서, 각각의 경우에 2개의 DNA 서열을 내부 리보좀 개시 부위의 DNA를 사용하여 서로 연결시킨, 수개의 동일하거나 상이한 항종양 물질의 DNA 서열을 포함하는 활성 화합물.
- 제1항 내지 제13항중 어느 한 항에 있어서, 벡터내로 삽입되는 활성 화합물.
- 제15항에 있어서, 벡터가 바이러스인 활성 화합물.
- 제16항에 있어서, 바이러스가 레트로바이러스, 아데노바이러스, 아데노-연합바이러스, 단순 포진 바이러스 또는 백시니아 바이러스인 활성 화합물.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 플가즈미드내로 삽입되는 활성 화합물.
- 제15항 내지 제18항 중 어느 한 항에 있어서, 콜로이드 분산 시스템내에서 제조되는 활성 화합물.
- 제19항에 있어서, 리포좀이 폴로이드 분산 시스템인 활성 화합물.
- 제20항에 있어서, 폴리라이신/리간드가 콜로이드 분산 시스템인 활성 화합물.
- 제15항 내지 제21항 중 어느 한 항에 있어서, 내피 세포의 막 구조와 결합하는 리간드를 보충시킨 활성 화합물.
- 제22항에 있어서, 리간드가, 가변 도메인(variable domain)에 의해 내피 세포의 막구조와 결합하는 이의 폴리클로날 또는 모노클로날 항체 또는 항체 단편이거나, 연근 세포상의 수용체와 결합하는, 사이토킨 또는 증식 인자, 또는 이의 단편 또는 구성 서열이거나 또는 SLeX, LFA-1, MAC-1, LECAM-1 또는 VLA-4과 같은 접착 분자인 활성 화합물.
- 제23항에 있어서, 내피 세포의 막구조가 만노즈, IL-1, 또는 PDGF, FGF, VEGF 또는 TGFβ와 같은 증식 인자에 대한 수용체인 활성 화합물.
- 제1항 내지 제24항 중 어느 한 항에 있어서, 정맥내, 동맥내 또는 와동내 주사용, 조직 또는 조직 사이 주사용 또는 국부 투여용 약제학적 제제형태의 활성 화합물.※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
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GB9417366A GB9417366D0 (en) | 1994-08-26 | 1994-08-26 | Cell cycle regulated repressor and DNA element |
GB9417366.3 | 1995-03-29 | ||
GB9506466.3 | 1995-03-29 | ||
GBGB9506466.3A GB9506466D0 (en) | 1994-08-26 | 1995-03-29 | Cell cycle regulated repressor and dna element |
PCT/EP1995/003370 WO1996006940A1 (de) | 1994-08-26 | 1995-08-25 | Gentherapeutische behandlung von tumoren mit einem endothelzellspezifischen, zellzyklusabhängigen wirkstoff |
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