Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors
Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors
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DOI：
10.1158/0008-5472.can-04-0919
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发表时间：
2004-09-01
期刊：
影响因子：
11.2
通讯作者：
Ochiai, A
中科院分区：
文献类型：
--
作者：
Goya, M;Miyamoto, S;Ochiai, A
晚期前列腺癌通常涉及胰岛素样生长因子 (IGF) 含量最高的骨骼。然而，由于缺乏可靠的动物模型，骨源性IGF在前列腺癌骨转移中的作用尚未得到广泛研究。因此，我们研究了一种针对人 IGF-I 和 IGF-II (KM1468) 的新型抗体是否可以抑制植入人类成人骨的非肥胖糖尿病/严重联合免疫缺陷小鼠中新骨肿瘤的发展和已形成骨肿瘤的进展。我们首先证实KM1468与人IGF-I、人IGF-II和小鼠IGF-II特异性结合，但不与胰岛素结合。它还阻断了过表达人 I 型 IGF 受体的 BALB/c 3T3 细胞中由 IGF 结合诱导的 I 型 IGF 受体的自身磷酸化，并在体外抑制了 IGF 刺激的 MDA PCa 2b 细胞生长。然后小鼠腹膜内注射KM1468，每周一次，持续4周，可以立即注射，也可以在接种MDA PCa 2b细胞后4周注射。通过组织形态计量学测定，KM1468 显着且剂量依赖性地抑制新骨肿瘤的发展和已建立的肿瘤灶的进展，并且与对照相比，它还降低了血清前列腺特异性抗原水平。这是 IGF 配体特异性抑制性抗体的首次报道，该抗体可抑制人类成年骨骼中前列腺癌细胞的生长。这些结果表明IGF信号轴是预防和治疗前列腺癌骨转移的潜在靶点。
Advanced prostate cancer frequently involves the bone that has the largest content of insulin-like growth factors (IGFs). However, the role of bone-derived IGFs in bone metastasis of prostate cancer has not been studied extensively because of the lack of a reliable animal model. Therefore, we investigated whether a novel antibody directed against human IGF-I and IGF-II (KM1468) could inhibit the development of new bone tumors and the progression of established bone tumors in nonobese diabetic/severe combined immunodeficient mice implanted with human adult bone. We first confirmed that KM1468 bound specifically to human IGF-I, human IGF-II, and mouse IGF-II but not to insulin. It also blocked autophosphorylation of the type I IGF receptor induced by the binding of IGFs in human-type I IGF receptor-overexpressing BALB/c 3T3 cells, and it inhibited the IGF-stimulated growth of MDA PCa 2b cells in vitro. Then mice were injected intraperitoneally with KM1468 once weekly for 4 weeks either immediately or 4 weeks after inoculation of MDA PCa 2b cells. KM1468 markedly and dose-dependently suppressed the development of new bone tumors and the progression of established tumor foci, as determined by histomorphometry, and it also decreased serum prostate-specific antigen levels, compared with the control. This is the first report of an IGF ligand-specific inhibitory antibody that suppresses the growth of human prostate cancer cells in human adult bone. These results indicate that the IGF signaling axis is a potential target for prevention and treatment of bone metastases arising from prostate cancer.