Department of Urology, School of Medicine, University of California-Los Angeles, Los Angeles, California 90095, USA.
Mol Cancer Ther. 2012 Jul;11(7):1539-46. doi: 10.1158/1535-7163.MCT-11-1003. Epub 2012 May 4.
In preclinical models, both dietary fat reduction and insulin-like growth factor I receptor (IGF-1R) blockade individually inhibit prostate cancer xenograft growth. We hypothesized that a low-fat diet combined with IGF-1R blockade would cause additive inhibition of prostate cancer growth and offset possible untoward metabolic effects of IGF-1R blockade antibody therapy. Fifty severe combined immunodeficient mice were injected with 22Rv1 cells subcutaneously. Ten days postinjection, the animals were randomized to four groups: (i) high-fat diet + saline (HF); (ii) high-fat diet + IGF-1R blocking antibody, ganitumab (HF/Ab); (iii) low-fat diet + saline (LF); and (iv) low-fat diet + ganitumab (LF/Ab). After 19 days of treatment, the animals were euthanized, serum was collected, and tumors were weighed. Tumor Ki67, Akt and extracellular signal-regulated kinase (ERK) activation, serum insulin, IGF-I and TNF-α were measured. In vitro, ganitumab treatment inhibited growth and induced apoptosis in several prostate cancer cell lines. In vivo, tumor weights and volumes were unaffected by the different treatments. The LF/Ab therapy significantly reduced proliferation (Ki67) and ERK activation in tumors. The HF/Ab group had significantly higher serum insulin levels than the HF group. However, LF/Ab combination significantly reduced serum insulin back to normal levels as well as normalizing serum TNF-α level. Whereas the combination of low-fat diet and IGF-1R blockade did not have additive inhibitory effects on tumor weight, it led to reduced tumor cell proliferation and a reduction in serum insulin and TNF-α levels.
在临床前模型中，减少饮食中的脂肪和胰岛素样生长因子 I 受体 (IGF-1R) 阻断都可以单独抑制前列腺癌异种移植物的生长。我们假设低脂肪饮食与 IGF-1R 阻断相结合会导致前列腺癌生长的附加抑制，并抵消 IGF-1R 阻断抗体治疗可能带来的不良代谢影响。50 只严重联合免疫缺陷小鼠皮下注射 22Rv1 细胞。注射后 10 天，将动物随机分为四组：（i）高脂肪饮食+生理盐水（HF）；（ii）高脂肪饮食+IGF-1R 阻断抗体，ganitumab（HF/Ab）；（iii）低脂肪饮食+生理盐水（LF）；和（iv）低脂肪饮食+ganitumab（LF/Ab）。治疗 19 天后，处死动物，采集血清，称重肿瘤。测量肿瘤 Ki67、Akt 和细胞外信号调节激酶（ERK）的激活、血清胰岛素、IGF-I 和 TNF-α。在体外，ganitumab 治疗抑制了几种前列腺癌细胞系的生长并诱导其凋亡。在体内，不同治疗方法对肿瘤重量和体积没有影响。LF/Ab 治疗显著降低了肿瘤的增殖（Ki67）和 ERK 激活。HF/Ab 组的血清胰岛素水平明显高于 HF 组。然而，LF/Ab 联合治疗显著降低了血清胰岛素水平，使其恢复正常，并使血清 TNF-α水平正常化。尽管低脂饮食和 IGF-1R 阻断的联合治疗对肿瘤重量没有附加抑制作用，但它导致肿瘤细胞增殖减少和血清胰岛素和 TNF-α水平降低。
