ROWTH hormone, which is secreted from the anteri- or pituitary gland, stimulates the synthesis of IGF- I in the liver and in many other tissues. The direct effects of GH and the indirect effects of IGF-1 combine to produce the changes associated with normal growth. In at least 20 years of both basic and clinical studies, 20 however, GH and IGF-I have also been identified as potent inducers of cell growth in many types of neoplasms. Examples of malignancies responsive to IGF-I include primary tumors of the breast, colon, and prostate. 3,19,28 Previously, in a series of in vitro experiments, we dem- onstrated that the GH/IGF-I axis is also important in mod- ulating meningioma growth. 9 Specifically, we performed a series of experiments in which the following were demon- strated: 1) that the GH receptor is ubiquitously expressed in meningiomas; 2) that blockade of the GH receptor by using the GH receptor antagonist pegvisomant (former- ly B2036-PEG) significantly decreases the growth rates of many primary meningioma cultures; and 3) that admin- istration of IGF-I significantly increases primary culture growth rates. These findings indicated that further experi- ments would be warranted to evaluate the therapeutic effi- cacy of GH receptor blockade by using an in vivo menin- gioma model, as is described in this manuscript. A number of different methods have been developed to study meningioma growth in vivo, including models in J. Neurosurg. / Volume 94 / March, 2001 J Neurosurg 94:487–492, 2001 Antitumor activity of the growth hormone receptor antagonist pegvisomant against human meningiomas in nude mice IAN E. MCCUTCHEON, M.D., ALLAN FLYVBJERG, M.D., HOLLY HILL, B.S., JESSICA LI, B.S., WILLIAM F. BENNETT , PH.D., JOHN A. SCARLETT , M.D., AND KEITH E. FRIEND, M.D. Department of Neurosurgery and Section of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; Medical Department M (Diabetes and Endocrinology) Aarhus Kommunehospital, Aarhus, Denmark; and Sensus Drug Development Corporation, Austin, Texas Object. 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. Methods. 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 pegvi- somant 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 mm 3 in the vehicle group and 291.1  20 mm 3 in the pegvisomant group. After 8 weeks of treatment, the mean volume of tumors in the pegvi- somant group was 198.3  18.9 mm 3 compared with 350.1  23.5 mm 3 for the vehicle group (p  0.001). The serum IGF-I concentration in the vehicle group was 319  12.9 g/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 lev- els, 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 peg- visomant or vehicle group. The IGF-II levels were highly variable (0–38.2 ng/g tissue) and did not differ significant- ly between treatment groups. Conclusions. 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 anti- tumor effect is most likely a decrease of IGF-I in the circulation and/or surrounding host tissues. Because the au- thors have previously demonstrated that the GH receptor is ubiquitously expressed in meningiomas, direct block- ade of the GH receptor on the tumors may also be contributing to inhibitory actions. KEY WORDS • meningioma • insulin-like growth factor • growth hormone • antagonist • mouse G 487 Abbreviations used in this paper: GH = growth hormone; IGFBP = insulin-like growth factor binding protein; SEM = stan- dard error of the mean.