McCutcheon I E, Flyvbjerg A, Hill H, Li J, Bennett W F, Scarlett J A, Friend K E
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, USA.
J Neurosurg. 2001 Mar;94(3):487-92. doi: 10.3171/jns.2001.94.3.0487.
The authors have previously demonstrated that modulation of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis can significantly affect meningioma growth in vitro. These studies were performed to evaluate the efficacy of GH receptor blockade in vivo.
Primary cultures from 15 meningioma tumors obtained in humans were xenografted into athymic mice. Approximately 1.5 million cells from each of the 15 tumors were implanted into the flanks of two female mice, one pair for each tumor. One animal from each of the 15 pairs was then treated with the GH receptor antagonist pegvisomant and the other with vehicle alone for 8 weeks. The tumor volume was measured using digital calipers three times per week. The mean tumor volume at the initiation of injections was 284 +/- 18.8 mm3 in the vehicle group and 291.1 +/- 20 mm3 in the pegvisomant group. After 8 weeks of treatment, the mean volume of tumors in the pegvisomant group was 198.3 +/- 18.9 mm3 compared with 350.1 +/- 23.5 mm3 for the vehicle group (p < 0.001). The serum IGF-I concentration in the vehicle group was 319 +/- 12.9 microg/L compared with 257 +/- 9.7 in the pegvisomant group (p < 0.02). A small but significant decrease was observed in circulating IGF binding protein (IGFBP)-3 levels, whereas slight increases occurred with respect to serum IGFBP-1 and IGFBP-4 levels. In the placebo group the tumor weight was 0.092 +/- 0.01 g compared with 0.057 +/- 0.01 g in the pegvisomant group (p < 0.02). The IGF-I and IGF-II concentrations were measured in the tumors by using a tissue extraction method. These human-specific immunoassays demonstrated that there was no autocrine production of IGF-I in any of the tumors, either in the pegvisomant or vehicle group. The IGF-I levels were highly variable (0-38.2 ng/g tissue) and did not differ significantly between treatment groups.
In an in vivo tumor model, downregulation of the GH/IGF-I axis significantly reduces meningioma growth and, in some instances, causes tumor regression. Because the concentrations of IGF-II in tumor did not vary with pegvisomant treatment and there was no autocrine IGF-I production by the tumors, the mechanism of the antitumor effect is most likely a decrease of IGF-I in the circulation and/or surrounding host tissues. Because the authors have previously demonstrated that the GH receptor is ubiquitously expressed in meningiomas, direct blockade of the GH receptor on the tumors may also be contributing to inhibitory actions.
作者先前已证明，生长激素（GH）/胰岛素样生长因子-I（IGF-I）轴的调节可在体外显著影响脑膜瘤生长。进行这些研究以评估GH受体阻断在体内的疗效。
将从15例人类脑膜瘤肿瘤获得的原代培养物异种移植到无胸腺小鼠体内。将15个肿瘤中每个肿瘤的约150万个细胞植入两只雌性小鼠的侧腹，每个肿瘤一对。然后，从15对中的每对中选取一只动物用GH受体拮抗剂培维索孟治疗，另一只用赋形剂单独治疗8周。每周用数字卡尺测量肿瘤体积3次。注射开始时，赋形剂组的平均肿瘤体积为284±18.8立方毫米，培维索孟组为291.1±20立方毫米。治疗8周后，培维索孟组肿瘤的平均体积为198.3±18.9立方毫米，而赋形剂组为350.1±23.5立方毫米（p<0.001）。赋形剂组的血清IGF-I浓度为319±12.9微克/升，培维索孟组为257±9.7微克/升（p<0.02）。循环中的IGF结合蛋白（IGFBP）-3水平出现了轻微但显著的下降，而血清IGFBP-1和IGFBP-4水平则略有升高。在安慰剂组中，肿瘤重量为0.092±0.01克，培维索孟组为0.057±0.01克（p<0.02）。采用组织提取法测量肿瘤中的IGF-I和IGF-II浓度。这些针对人类的免疫测定表明，在培维索孟组或赋形剂组的任何肿瘤中均未检测到IGF-I的自分泌产生。IGF-I水平变化很大（0-38.2纳克/克组织），治疗组之间无显著差异。
在体内肿瘤模型中，GH/IGF-I轴的下调显著降低脑膜瘤生长，在某些情况下可导致肿瘤消退。由于肿瘤中的IGF-II浓度在培维索孟治疗后未发生变化，且肿瘤未产生自分泌IGF-I，因此抗肿瘤作用的机制很可能是循环中和/或周围宿主组织中IGF-I的减少。由于作者先前已证明GH受体在脑膜瘤中普遍表达，直接阻断肿瘤上的GH受体也可能有助于发挥抑制作用。
