Antitumor activity of the growth hormone receptor antagonist pegvisomant against human meningiomas in nude mice

Object. The authors have previously demonstrated that modulation of the gro wth hormone (GH)/insulin-like growth factor-I (IGF-I) axis can significantl y affect meningioma growth in vitro. These studies were performed to evalua te 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 o f the lj tumors were implanted into the flanks of two female mice, one pair for each tumor. One animal from each of the lj pairs was then treated with the GH receptor antagonist pegvisomant and the other with vehicle alone fo r 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 pegvis omant 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 vehicl e group was 319 +/- 12.9 <mu>g/L compared with 257 +/- 9.7 in the pegvisoma nt group (p < 0.02). A small but significant decrease was observed in circu lating IGF binding protein (IGFBP)-3 levels, whereas slight increases occur red 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 mea sured in the tumors by using a tissue extraction method. These human-specif ic 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 -II levels were highly variable (0-38.2 ng/g tissue) and did not differ sig nificant ly between treatment groups. Conclusion. In an in vivo tumor model, downregulation of the GH/IGF-I axis significantly reduces meningioma growth and, in some instances, causes tumo r regression. Because the concentrations of IGF-II in tumor did not vary wi th 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 auth ors have previously demonstrated that the CH receptor is ubiquitously expre ssed in meningiomas, direct blockade of the GH receptor on the tumors may a lso be contributing to inhibitory actions.