Ye J-J, Liang S-J, Guo N, Li S-L, Wu A M, Giannini S, Sachdev D, Yee D, Brünner N, Ikle D, Fujita-Yamaguchi Y
Department of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Horm Metab Res. 2003 Nov-Dec;35(11-12):836-42. doi: 10.1055/s-2004-814145.
Proliferative and anti-apoptotic actions of IGFs are mediated by the IGF-I receptor (IGF-IR), to which both IGF-I and -II bind with high affinity. We previously reported that alphaIGF-IR scFv-Fc (scFv-Fc) consisting of the alphaIGF-IR scFv and human IgG (1) Fc domain retained general characteristics of the parental 1H7 monoclonal antibody, and significantly suppressed MCF-7 tumor growth. We proposed IGF-IR down-regulation as a possible mechanism for inhibition of MCF-7 tumor growth. To further determine the therapeutic potentials of this approach, in vivo effects of this antibody on breast tumor growth were evaluated in the absence or presence of tamoxifen (Tam) using a T61 human breast tumor model. T61 xenograft growth in athymic mice was compared under five conditions, PBS, scFv-Fc, Tam, scFv-Fc+Tam, and control antibody. While treatment with PBS and control antibody did not affect T61 tumor growth, scFv-Fc, Tam, and scFv-Fc+Tam treatments significantly suppressed the tumor growth during the first two weeks of treatment. Although the growth inhibitory effect of scFv-Fc during the first two weeks was significant, the tumor grew as rapidly as PBS-treated tumors thereafter. This rapid tumor growth was suppressed when scFv-Fc was combined with Tam. Throughout four weeks, the combined Tam+scFv-Fc treatment was more effective in inhibiting the T61 tumor growth than scFv-Fc or Tam treatment alone. scFv-Fc treatment down-regulated IGF-IR which appears to contribute to tumor growth inhibition. This study provides evidence that simultaneous targeting of IGF-IR and the estrogen receptor may enhance the therapeutic effect.
胰岛素样生长因子（IGFs）的增殖和抗凋亡作用是由胰岛素样生长因子I受体（IGF-IR）介导的，IGF-I和-II均可与其高亲和力结合。我们之前报道过，由αIGF-IR单链抗体片段（scFv）和人IgG（1）Fc结构域组成的αIGF-IR scFv-Fc保留了亲本1H7单克隆抗体的一般特性，并显著抑制了MCF-7肿瘤的生长。我们提出IGF-IR下调可能是抑制MCF-7肿瘤生长的一种机制。为了进一步确定这种方法的治疗潜力，我们使用T61人乳腺肿瘤模型，在有无他莫昔芬（Tam）的情况下评估了该抗体对乳腺肿瘤生长的体内作用。在五种条件下比较了无胸腺小鼠体内T61异种移植物的生长情况，即磷酸盐缓冲盐水（PBS）、scFv-Fc、Tam、scFv-Fc+Tam和对照抗体。虽然用PBS和对照抗体处理不影响T61肿瘤的生长，但scFv-Fc、Tam和scFv-Fc+Tam处理在治疗的前两周显著抑制了肿瘤生长。尽管scFv-Fc在前两周的生长抑制作用显著，但此后肿瘤生长速度与PBS处理的肿瘤一样快。当scFv-Fc与Tam联合使用时，这种快速的肿瘤生长受到了抑制。在整个四周时间里，联合使用Tam+scFv-Fc治疗在抑制T61肿瘤生长方面比单独使用scFv-Fc或Tam治疗更有效。scFv-Fc处理下调了IGF-IR，这似乎有助于抑制肿瘤生长。这项研究提供了证据表明，同时靶向IGF-IR和雌激素受体可能会增强治疗效果。
