KR102490334B1 - 암 치료용 아젤니디핀 약학 조성물의 새로운 적응증 - Google Patents

암 치료용 아젤니디핀 약학 조성물의 새로운 적응증 Download PDF

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KR102490334B1
KR102490334B1 KR1020177011094A KR20177011094A KR102490334B1 KR 102490334 B1 KR102490334 B1 KR 102490334B1 KR 1020177011094 A KR1020177011094 A KR 1020177011094A KR 20177011094 A KR20177011094 A KR 20177011094A KR 102490334 B1 KR102490334 B1 KR 102490334B1
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cancer
azelnidipine
pharmaceutical composition
cells
inhibition test
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KR20170084034A (ko
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츄-훙 천
쇼-메이 촹
쫑-더 웨이
나이-완 샤오
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라운크스 바이오메디컬 컴퍼니 리미티드
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Abstract

본 발명은 아젤니디핀(Azelnidipine)의 새로운 적응증에 관한 것이다. 아젤니디핀은 이미 FDA로부터 승인되었다. 본 발명은 다양한 암세포를 효과적으로 치료하기 위한 아젤니디핀 약학 조성물을 제공한다.

Description

암 치료용 아젤니디핀 약학 조성물의 새로운 적응증{NEW INDICATION OF AZELNIDIPINE PHARMACEUTICAL COMPOSITION FOR TREATING CANCER}
본 발명은 아젤니디핀(Azelnidipine) 약학 조성물의 새로운 적응증에 관한 것으로, 특히 다양한 암 세포에 대한 아젤니디핀 약학 조성물의 억제 효과에 관한 것이다.
아젤니디핀은 고혈압 치료제로서, 단독으로 또는 다른 항고혈압제와 조합하여 사용될 수 있다. 아젤니디핀은 FDA로부터 승인되었고, 약의 용도 및 약리기전 조사에 대한 방대한 자료가 축적되어 있다.
임상적 용도의 차이로 인해, 현재까지 아젤니디핀의 암세포 억제 가능성에 대해 제시하고 있는 연구는 없다.
한편 암은 세계에서 사망의 원인이 되는 가장 대중적인 질병이다. 암 환자는 매년 점차적으로 증가하므로 암 치료 방법이 중요한 문제로 대두되고 있다. 의학적 암 치료는 외과적 치료, 방사선 치료, 화학 요법 및 표적 치료로 분류할 수 있다. 일반적으로 항암제는 화학 요법 약물이든 표적 치료제이든 상관없이 암 세포의 복제를 억제하여 종양의 성장과 전이를 방지한다. 평균적으로, 약 10,000분의 5개의 신약만이 성공적으로 임상 시험 Ⅰ 단계에 진입할 수 있다. 또한, 암 환자가 약물 내성을 일으킨다면, 이는 약물의 효과를 감소시키고 치료 실패를 초래할 수 있다. 따라서 신약 개발은 매우 어렵다.
그러므로, 항암제를 신속하게 개발하고 다양한 암 치료에 대한 임상적 실패 가능성을 줄이는 방법을 강구하는 것은 매우 시급하고 중요한 문제이다.
상술한 문제점을 해결하기 위하여, 본 발명은 아젤니디핀의 새로운 암 임상 적응증의 개발에 대해 제공한다.
따라서, 본 발명은 아젤니디핀의 새로운 적응증을 제공한다. 본 발명의 실험 결과는 아젤니디핀이 정상세포에 대해 독성이 없거나 독성이 거의 없음을 보여주었다. 그러나 정상 세포와 암세포 사이의 아젤니디핀의 선택적 효과는 확인될 필요가 있다.
본 발명은 암 치료를 위한 아젤니디핀의 약학 조성물을 제공한다. 상기 약학 조성물은 유효 투여량의 아젤니디핀 및 약학적으로 허용 가능한 염으로 구성된다.
본 발명의 일 실시예에서, 상기 암은 흉막-관련 암, 복부-관련 암, 내분비계-관련 암, 위장관-관련 암으로부터 선택된다.
본 발명의 일 실시예에서, 상기 암은 골육종, 피부암 및 혈액암으로부터 선택된다.
본 발명의 일 실시예에서, 상기 흉막-관련 암은 폐암이다.
본 발명의 일 실시예에서, 상기 복부-관련 암은 방광암, 자궁경부암으로부터 선택된다.
본 발명의 일 실시예에서, 상기 내분비계-관련 암은 전립선암, 유방암 및 난소암으로부터 선택된다.
본 발명의 일 실시예에서, 위장관-관련 암은 위암, 간암, 결장직장암, 췌장암 및 설암으로부터 선택된다.
본 발명의 일 실시예에서, 아젤니디핀의 유효 투여량은 20 mg/kg/day 내지 500 mg/kg/day 이다.
도1은 각기 다른 암세포에 아젤니디핀이 미치는 억제 효과 결과를 보여준다.
도2는 아젤니디핀에 의한 종양 부피의 억제 효과 결과를 보여준다.
도3은 고용량 및 저용량으로 투여된 아젤니디핀을 통한 종양 성장 억제 효과 결과를 보여준다.
세포 배양
암세포주의 각기 다른 종류는 계대배양(subculture)한다. 상기 암세포는 폐암, 위암, 간암, 대장암, 피부암, 자궁경부암, 전립선암, 방광암, 유방암, 백혈병, 췌장암, 난소암, 설암, 골육종 및 신장암을 포함한다. 대조군에서 사용되는 정상 세포들은 신장 세포(HEK293) 및 사람 기관지 상피세포주 BEAS-2B(표1에서 보는 바와 같음)를 포함했다.
암세포주는 각기 다른 특성 때문에 각각 다른 배지에서 배양하였다(표1에서 보는 바와 같음). 세포 수는 계수하여 셀 배양 판/플라스크에서 2×106으로 재접종(reseed)하였다. 그 후, 상기 배지를 10ml의 부피로 첨가하고, 세포를 2일 내지 3일 동안 배양하였다. 그 후, 세포를 96-웰 플레이트(well plate)에 로딩(loading)하기 위해 부유시켰다. 상기 세포 수는 3000이었고, 상기 배지의 부피는 각 웰(well)당 100㎕였다.
Figure 112017060489289-pct00001
세포 생존능력 분석
96-웰 플레이트에서 원 배지를 제거한다. 그런 다음 웰당 10μM의 농도로 100㎕의 상업적으로 입수가능한 약물을 첨가한다. 72시간 후 희석된 WST-1 시약을 100㎕/웰로 웰에 첨가하고, 상기 희석된 WST-1 시약은 9:1 배지 및 WST-1 스톡(stock)시약의 희석액으로부터 수득하였다. 마지막으로, 각 웰의 총 부피는 200㎕/웰 이었다. 96-웰 플레이트를 37 ℃에서 30분 내지 90분 동안 배양한다. ELISA 판독기로 OD450nm에서, 각 암세포의 생존율을 검출하고 계산한다.
다른 암세포주에 대한 아젤니디핀의 효과
흉막-관련 암세포에 대한 아젤니디핀의 억제 효과
흉막-관련 암세포에 대한 아젤니디핀의 억제 시험에서는, 두 가지의 폐암 세포주로 A549 및 H1650가 사용되었다. 아젤니디핀의 억제 시험은 각 세포주에 대해 4번씩 수행되었고, 억제 시험의 평균값을 계산했다. 그 결과를 하기 표에 나타내었다.
Figure 112017060489289-pct00002
복부-관련 암세포주에 대한 아젤니디핀의 억제 효과
복부-관련 암세포에 대한 아젤니디핀의 억제 시험에서는, 방광암 세포주로 TSGH 및 T24(표3)가, 자궁경부암 세포주로 HeLa 및 C-33A(표4)가, 신장암 세포주로 786-0(표5)가 사용되었다. 아젤니디핀의 억제 시험은 각 세포주에 대해 4번씩 수행되었고, 억제 시험의 평균값을 계산했다. 그 결과를 하기 표에 나타내었다.
Figure 112017060489289-pct00003
Figure 112020106367469-pct00022
Figure 112017060489289-pct00005
내분비계-관련 암세포주에 대한 아젤니디핀의 억제 효과
내분비계-관련 암세포에 대한 아젤니디핀의 억제 시험에서는, 전립선암 세포주로 PC-3(표6)이, 유방암주로 MCF7 및 MDA-MB-231(표7)이, 난소암 세포주로 NIH-OVCAR-3 및 TOV-21G(표8)가 사용되었다. 아젤니디핀의 억제 시험은 각 세포주에 대해 4번씩 수행되었고, 억제 시험의 평균값을 계산했다. 그 결과를 하기 표에 나타내었다.
Figure 112017060489289-pct00006
Figure 112017060489289-pct00007
Figure 112017060489289-pct00008
위장관-관련 암세포주에 대한 아젤니디핀의 억제 효과
위장관-관련 암세포에 대한 아젤니디핀의 억제 시험에서는, 위암 세포주로 AGS 및 MKN-45(표9)가, 간암 세포주로 HepG2 및 Hep3B(표10)가, 결장직장암 세포주로 HCT116-wt 및 LoVo(표11)가, 췌장암 세포주로 AsPC-1 및 BxPC-3(표12)이, 설암 세포주로 SAS(표13)가 사용되었다. 아젤니디핀의 억제 시험은 각 세포주에 대해 4번씩 수행되었고, 억제 시험의 평균값을 계산했다. 그 결과를 하기 표에 나타내었다.
Figure 112017060489289-pct00009
Figure 112017060489289-pct00010
Figure 112017060489289-pct00011
Figure 112017060489289-pct00012
Figure 112017060489289-pct00013
그 외의 다른 암세포주에 대한 아젤니디핀의 억제 효과
그 외의 다른 암세포에 대한 아젤니디핀의 억제 시험에서는, 골육종 세포주로 U2OS(표14)가, 피부암 세포주로 A375 및 BCC(표15)가 사용되었다. 아젤니디핀의 억제 시험은 각 세포주에 대해 3번 내지 4번씩 수행되었고, 억제 시험의 평균값을 계산했다. 그 결과를 하기 표에 나타내었다.
Figure 112017060489289-pct00014
Figure 112017060489289-pct00015
대조군에 대한 실험 설계
정상 세포에 대한 아젤니디핀의 억제 효과
정상 세포에 대한 아젤니디핀의 억제 시험에서는, 정상 신장 세포주로 HEK293(표16)이, 정상 폐 상피세포주로 BEAS-2B(표17)가 사용되었다. 아젤니디핀의 억제 시험은 각 세포주에 대해 4번씩 수행되었고, 억제 시험의 평균값을 계산했다. 그 결과를 하기 표에 나타내었다.
Figure 112017060489289-pct00016
Figure 112017060489289-pct00017
모든 종류의 세포에 대한 아젤니디핀의 억제 시험 결과를 표 18에 나타내었다. 아젤니디핀이 여러 암 세포주에 유의미한 억제 효과를 갖는다는 것은 명백하다. 본 발명의 실험 결과와 같다. 파록세틴(Paroxetine)은 다양한 암세포에 유의미한 억제 효과를 갖는다 (도1).
Figure 112017060489289-pct00018
투여량 100 mg /kg/day 및 200 mg /kg/ day 의 난소암 동물 모델 시험
본 발명에서, 암컷 생쥐(BALB/cAnN.Cg-Foxn1nu/CrlNarl)는 국립 실험 동물 센터(대만)로부터 구입하였다. 생쥐의 무게는 21±1g이었다. 이 생쥐에게 위암 세포(AGS)를 피하 주사한 다음, 생쥐를 무작위로 다른 케이지(cage)에 넣었다. 약물 검사 실험은 "정상 대조군", "저용량 군(100mg/kg/day)"및 "고용량 군(200mg/kg/day)"으로 세 그룹으로 나누었다. 이 생쥐에게 종양 크기가 100mm3에 도달할 때까지 1일 1회 복강 내로 시험 약물을 주입했다. 종양 크기와 체중을 일주일에 두 번 측정했다. 종양 크기는 다음 식에 의해 측정하고 계산했다 : (L×W2). L은 종양의 최장 길이를 나타낸다. W는 종양의 최단 직경을 나타낸다. 실험 결과를 표 19에 나타냈다.
Figure 112017060489289-pct00019
Figure 112017060489289-pct00020
도2의 결과에 따르면, 저용량 및 고용량의 아젤니디핀은 종양 세포에 유의미한 억제 효과를 나타냈다. 반면, 실험 중 생쥐의 무게는 유의미한 감소를 보이지 않았다. 이 결과는 아젤니디핀을 고용량 및 저용량으로 투여한 경우, 실험 생쥐를 치료하는 동안 죽지 않고 건강한 상태로 유지할 수 있음을 나타냈다.
도3의 결과에 따르면, 저용량 및 고용량의 아젤니디핀은 종양 부피 성장을 효과적으로 늦추고, 또한 종양 부피를 감소시킬 수 있다. 특히 고용량의 CellCept는 종양 성장 억제 효과가 더 컸다.
본 발명은 특정 예시적인 실시예 및 예시와 관련하여 기재되어 있더라도, 본 명세서에 개시된 실시예는 단지 예시적 목적을 위한 것이며, 본 기술 분야의 당업자는 하기 청구범위에 기재된 본 발명의 사상 및 범위를 벗어나지 않고 다양한 수정 및 변형을 행할 수 있다는 것을 이해할 것이다.

Claims (8)

  1. 치료적 유효량의 아젤니디핀(Azelnidipine) 또는 이의 약학적으로 허용 가능한 염을 포함하는 암 치료용 약학 조성물로서,
    상기 암은 비소세포 폐암, 난소암(ovarian cancer), 췌장암(pancreatic cancer), 설암(tongue cancer) 및 골육종(osteosarcoma)으로부터 선택되는, 약학 조성물.
  2. 제1항에 있어서,
    상기 아젤니디핀의 유효량은 20mg/kg/day 내지 500mg/kg/day인, 약학 조성물.
  3. 삭제
  4. 삭제
  5. 삭제
  6. 삭제
  7. 삭제
  8. 삭제
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