Redondo-Müller M A, Stevanovic-Walker M, Barker S, Puddefoot J R, Vinson G P
School of Biological and Chemical Sciences, Queen Mary, University of London, London, UK.
Endocr Relat Cancer. 2008 Mar;15(1):277-88. doi: 10.1677/ERC-07-0068.
Although several tumour types express both AT1 and AT2 angiotensin II receptors, and angiotensin II stimulates cell proliferation, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are not effective anti-cancer agents. Development of a biologically active monoclonal antibody (6313/G2) against the AT1 receptor prompted the testing of a recombinant short-chain variable fragment form (R6313/G2) against breast cancer cells in vitro and in vivo. Cell lines MCF-7, MDA-MB-231 and T47D all expressed both receptor subtypes. In vitro, R6313/G2 suppressed cell proliferation in the presence of 100 nM angiotensin II, with IC50s of 30 nM, 153 nM and 2.8 microM for the three cell types respectively; in contrast, the AT1 receptor blocker losartan was effective only in T47D cells, at 25 microM. Studies on MCF-7 and T47D cells showed R6313/G2 also opposed the angiotensin II-induced inhibition of caspase-3/7 activity. In vivo, hollow fibres containing the cell lines were implanted in nu/nu balb-c mice at two sites, s.c. and i.p. Treatments of R6313/G2 at 2.5 nmol/kg and 25 nmol/kg twice per day for 7 days dose dependently reduced cell numbers for all three cell lines, but here MCF-7 cells responded most sensitively and MDA-MB-231 cells least. Although T47D cells were refractory at the s.c. site, growth was inhibited at the i.p. location, and otherwise results were similar at the two sites. In xenografts, MCF-7 cell tumours were dose dependently reduced by R6313/G2, and 13 and 27 nmol/kg R6313/G2 twice/day gave means of 74 and 76% tumour regression after 7 days. The data suggest that the anti-cancer action of R6313/G2 is considerably more effective than AT1 antagonists.
尽管多种肿瘤类型都表达1型和2型血管紧张素II受体，且血管紧张素II能刺激细胞增殖，但血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂并非有效的抗癌药物。一种针对1型受体的生物活性单克隆抗体（6313/G2）的研发促使人们对其重组短链可变片段形式（R6313/G2）在体外和体内针对乳腺癌细胞进行测试。MCF-7、MDA-MB-231和T47D细胞系均表达这两种受体亚型。在体外，R6313/G2在存在100 nM血管紧张素II的情况下抑制细胞增殖，这三种细胞类型的半数抑制浓度（IC50）分别为30 nM、153 nM和2.8 μM；相比之下，1型受体阻滞剂氯沙坦仅在T47D细胞中有效，浓度为25 μM。对MCF-7和T47D细胞的研究表明，R6313/G2还能对抗血管紧张素II诱导的半胱天冬酶-3/7活性抑制。在体内，将含有这些细胞系的中空纤维分别皮下和腹腔内植入无胸腺裸鼠的两个部位。以2.5 nmol/kg和25 nmol/kg的剂量每天两次给予R6313/G2处理7天，能剂量依赖性地减少所有三种细胞系的细胞数量，但在此处MCF-7细胞反应最敏感，MDA-MB-231细胞最不敏感。尽管T47D细胞在皮下部位难治，但在腹腔内位置其生长受到抑制，而且在这两个部位的其他结果相似。在异种移植中，R6313/G2能剂量依赖性地减少MCF-7细胞肿瘤，每天两次给予13和27 nmol/kg的R6313/G2，7天后肿瘤消退均值分别为74%和76%。数据表明，R6313/G2的抗癌作用比1型拮抗剂有效得多。
