Novel small molecule alpha v integrin antagonists: comparative anti-cancer efficacy with known angiogenesis inhibitors.
Novel small molecule alpha v integrin antagonists: comparative anti-cancer efficacy with known angiogenesis inhibitors.
复制标题
新型小分子αv整合素拮抗剂：与已知血管生成抑制剂的抗癌功效比较。
作者：
Janet S Kerr;Roseanne S Wexler;Shaker A. Mousa;Robinson Cs;E. J. Wexler;S. Mohamed;Voss Me;Devenny Jj;Czerniak Pm;A. Gudzelak;Andrew M. Slee
最近的证据支持整联蛋白参与血管生成：α v β 3和α v β 5整联蛋白的阻断破坏血管生成，导致血管形成减少，从而减少肿瘤生长。我们假设av拮抗剂可以抑制缺乏α v β 3整联蛋白的肿瘤细胞的肿瘤生长。我们评估了SM 256和SD 983，这两种新型小分子是血管生成和肿瘤发生小鼠模型中的特异性av拮抗剂，并将它们与标准品进行了比较：TNP 470，一种临床上的烟曲霉素类似物，和flavopiridol，一种细胞周期激酶抑制剂。在体外，SM 256是一种选择性α v β 3抑制剂，IC 50 = 4 nM，SD 983对小鼠内皮α v β 3整联蛋白的亲和力产生的IC 50 = 2 nM，对α v β 5的IC 50 = 54 nM。在血管生成的小鼠Matrigel模型中，SM 256降低了血管形成（血红蛋白含量），ED 50 = 0.055 ug/kg/天，比TNP 470强10倍。SD 983的酯SG 545可减少血管形成，ED 50 = 6 ug/kg/天，而flavopiridol ED 50 = 18 ug/kg/天。在小鼠异种移植模型中，使用不表达α v β 3但表达α v β 5的人结肠癌RKO细胞，SG 545（10 mg/kg/天）和flavopiridol（5 mg/kg/隔天）分别抑制肿瘤生长40%和70%（p < 0.05）。尽管SM 256、SG 545或flavopiridol（29-32%）未显著改变增殖指数（通过BrdU掺入测量），但与对照组（1.1%）相比，SM 256和SG 545处理组（2.3-2.7%）的凋亡指数显著增加（p < 0.05），表明细胞死亡增加有助于肿瘤体积减小。SM 256和SG 545治疗可减少新生血管形成。这些数据表明，强效的选择性av拮抗剂可以靶向内皮细胞、肿瘤细胞，抑制血管生成并抑制肿瘤生长。
Recent evidence supports the involvement of integrins in angiogenesis: blockade of alpha v beta 3 and alpha v beta 5 integrins disrupts angiogenesis leading to decreased blood vessel formation and hence decreased tumor growth. We hypothesized that av antagonists could inhibit tumor growth in tumor cells devoid of alpha v beta 3 integrins. We evaluated SM256 and SD983, novel small molecules that are specific av antagonists in mouse models of angiogenesis and tumorigenesis, and compared them with standards: TNP470, a fumagillin analog in the clinic, and flavopiridol, a cell cycle kinase inhibitor. In vitro SM256 was a selective alpha v beta 3 inhibitor with an IC50 = 4nM, and the affinity of SD983 against the mouse endothelial alpha v beta 3 integrin yielded an IC50 = 2nM and an IC50 = 54nM against alpha v beta 5. In the mouse Matrigel model of angiogenesis SM256 decreased blood vessel formation (hemoglobin content) with an ED50 = 0.055 ug/kg/day, tenfold more potent than TNP470. SG545, an ester of SD983, decreased blood vessel formation with an ED50 = 6 ug/kg/day, while flavopiridol ED50 = 18 ug/kg/day. In the mouse xenograft model, using human colon carcinoma RKO cells that do not express alpha v beta 3 but express alpha v beta 5, tumor growth was inhibited by SG545 (10 mg/kg/day) and flavopiridol (5 mg/kg/every other day) 40% and 70%, respectively (p < 0.05). Although the proliferative index (measured by BrdU incorporation) was not significantly changed with SM256, SG545 or flavopiridol (29-32%), the apoptotic index increased significantly (p < 0.05) in the SM256 and SG545-treated groups (2.3-2.7%) compared with controls (1.1%), suggesting increased cell death contributed to decreased tumor volumes. Neovascularization decreased with SM256 and SG545 treatment. The data demonstrate that potent selective av antagonist can target endothelial cells, tumor cells, inhibit angiogenesis and inhibit tumor growth.