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

2001 ◽  
Vol 94 (3) ◽  
pp. 487-492 ◽  
Author(s):  
Ian E. McCutcheon ◽  
Allan Flyvbjerg ◽  
Holly Hill ◽  
Jessica Li ◽  
William F. Bennett ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Receptor Antagonist ◽  
Tumor Volume ◽  
Vehicle Group ◽  
Content Type ◽  
Gh Receptor ◽  
Igf I ◽  
The Mean ◽  
Fine Print

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 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 µg/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-II levels were highly variable (0–38.2 ng/g tissue) and did not differ significantly 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 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.

Growth hormone receptor expression and function in meningiomas: effect of a specific receptor antagonist

1999 ◽  
Vol 91 (1) ◽  
pp. 93-99 ◽  
Author(s):  
Keith E. Friend ◽  
Robert Radinsky ◽  
Ian E. McCutcheon
Keyword(s):  
Growth Hormone ◽  
Growth Rate ◽  
Receptor Antagonist ◽  
Messenger Rna ◽  
Thymidine Incorporation ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Content Type ◽  
Gh Receptor ◽  
Fine Print

Object. This study was undertaken to explore the effects of growth hormone (GH) and the GH-stimulated peptide insulin-like growth factor—1 (IGF-1) on the growth rate of meningiomas.Methods. Polymerase chain reaction and ribonuclease protection assays were used to demonstrate that GH receptor messenger RNA was present in all 14 meningioma specimens studied, regardless of tumor grade. Both wild type (GHRwt) and a previously described exon 3 deletion isoform (GHRd3) of the GH receptor were identified in individual tumor specimens. The importance of the GH receptor was assessed using a GH receptor antagonist (B2036). Blockade of the GH receptor with B2036 reduced serum-induced DNA synthesis, as measured by thymidine incorporation, by 8 to 33% (mean 20%) in primary meningioma cultures. Tumors that expressed the GHRwt and GHRd3 isoforms, or a combination of the two, were all responsive to antagonist treatment. The importance of IGF-1 in stimulating meningioma cell growth was also assessed. It was found that IGF-1 increased thymidine incorporation in primary meningioma cultures in a dose-dependent manner: 1 ng/ml, 5 ng/ml, and 10 ng/ml resulted in increases in thymidine incorporation of 21%, 43%, and 176%, respectively, over baseline values.Conclusions. In these studies the authors demonstrate that activation of the GH/IGF-1 axis significantly increases the growth rate of meningiomas. Blockade of the GH receptor on tumor cells inhibited tumor growth. If these findings are confirmed in animal studies, agents that downregulate the GH/IGF-1 axis might represent a potential adjuvant therapy in the management of patients with meningioma.

Gamma knife radiosurgery for craniopharyngiomas

2000 ◽  
Vol 93 (supplement_3) ◽  
pp. 47-56 ◽  
Author(s):  
Wen-Yuh Chung ◽  
David Hung-Chi Pan ◽  
Cheng-Ying Shiau ◽  
Wan-Yuo Guo ◽  
Ling-Wei Wang
Keyword(s):  
Clinical Outcome ◽  
Gamma Knife ◽  
Tumor Volume ◽  
Gamma Knife Radiosurgery ◽  
Tumor Control ◽  
Content Type ◽  
Stereotactic Aspiration ◽  
Cystic Component ◽  
The Mean ◽  
Fine Print

Object. The goal of this study was to elucidate the role of gamma knife radiosurgery (GKS) and adjuvant stereotactic procedures by assessing the outcome of 31 consecutive patients harboring craniopharyngiomas treated between March 1993 and December 1999. Methods. There were 31 consecutive patients with craniopharyngiomas: 18 were men and 13 were women. The mean age was 32 years (range 3–69 years). The mean tumor volume was 9 cm3 (range 0.3–28 cm3). The prescription dose to the tumor margin varied from 9.5 to 16 Gy. The visual pathways received 8 Gy or less. Three patients underwent stereotactic aspiration to decompress the cystic component before GKS. The tumor response was classified by percentage reduction of tumor volume as calculated based on magnetic resonance imaging studies. Clinical outcome was evaluated according to improvement and dependence on replacement therapy. An initial postoperative volume increase with enlargement of a cystic component was found in three patients. They were treated by adjuvant stereotactic aspiration and/or Ommaya reservoir implantation. Tumor control was achieved in 87% of patients and 84% had fair to excellent clinical outcome in an average follow-up period of 36 months. Treatment failure due to uncontrolled tumor progression was seen in four patients at 26, 33, 49, and 55 months, respectively, after GKS. Only one patient was found to have a mildly restricted visual field; no additional endocrinological impairment or neurological deterioration could be attributed to the treatment. There was no treatment-related mortality. Conclusions. Multimodality management of patients with craniopharyngiomas seemed to provide a better quality of patient survival and greater long-term tumor control. It is suggested that GKS accompanied by adjuvant stereotactic procedures should be used as an alternative in treating recurrent or residual craniopharyngiomas if further microsurgical excision cannot promise a cure.

Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo

1994 ◽  
Vol 80 (3) ◽  
pp. 527-534 ◽  
Author(s):  
Yasuhiro Matsuda ◽  
Keiichi Kawamoto ◽  
Katsuzo Kiya ◽  
Kaoru Kurisu ◽  
Kazuhiko Sugiyama ◽  
...  
Keyword(s):  
Marked Reduction ◽  
Tumor Volume ◽  
Collagen Gel ◽  
Antitumor Effects ◽  
Histological Changes ◽  
Content Type ◽  
The Relationship ◽  
Fine Print

✓ The presence of the progesterone receptor (PR) in meningioma tissue has been confirmed by previous investigations. Studies have shown that the antiprogesterone drug, mifepristone, is a potent agent that inhibits the growth of cultured meningioma cells and reduces the size of meningiomas in experimental animal models and humans. However, these studies have not fully examined the relationship between the antitumor effects of an antiprogesterone agent and the expression of the PR. The present study examined the antitumor effects of mifepristone and a new potent antiprogesterone agent, onapristone; a correlation between the antitumor effects of these antiprogesterones and the presence of PR's in meningiomas in vitro and in vivo was also investigated. Meningioma tissue surgically removed from 13 patients was used in this study. In the in vitro arm of the study, mifepristone and onapristone exhibited cytostatic and cytocidal effects against cultured meningioma cells, regardless of the presence or absence of PR's; however, three PR-negative meningiomas showed no response to any dose of mifepristone and/or onapristone. In the in vivo arm, meningioma cells, embedded in a collagen gel, were implanted into the renal capsules of nude mice. Antiprogesterone treatment resulted in a marked reduction of the tumor volume regardless of the presence or absence of PR's. No histological changes in the meningioma cells suggestive of necrosis or apoptosis were detected in any of the mice treated with antiprogesterones. These findings suggest that mifepristone and onapristone have an antitumor effect against meningioma cells via the PR's and/or another receptor, such as the glucocorticoid receptor.

Long-term results of gamma knife surgery for growth hormone—producing pituitary adenoma: is the disease difficult to cure?

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 119-123 ◽  
Author(s):  
Tatsuya Kobayashi ◽  
Yoshimasa Mori ◽  
Yukio Uchiyama ◽  
Yoshihisa Kida ◽  
Shigeru Fujitani
Keyword(s):  
Growth Hormone ◽  
Gamma Knife ◽  
Pituitary Adenomas ◽  
Gamma Knife Surgery ◽  
Long Term Results ◽  
Content Type ◽  
The Mean ◽  
Dose Radiation ◽  
Fine Print

Object. The authors conducted a study to determine the long-term results of gamma knife surgery for residual or recurrent growth hormine (GH)—producing pituitary adenomas and to compare the results with those after treatment of other pituitary adenomas. Methods. The series consisted of 67 patients. The mean tumor diameter was 19.2 mm and volume was 5.4 cm3. The mean maximum dose was 35.3 Gy and the mean margin dose was 18.9 Gy. The mean follow-up duration was 63.3 months (range 13–142 months). The tumor resolution rate was 2%, the response rate 68.3%, and the control rate 100%. Growth hormone normalization (GH < 1.0 ng/ml) was found in 4.8%, nearly normal (< 2.0 ng/ml) in 11.9%, significantly decreased (< 5.0 ng/ml) in 23.8%, decreased in 21.4%, unchanged in 21.4%, and increased in 16.7%. Serum insulin-like growth factor (IGF)—1 was significantly decreased (IGF-1 < 400 ng/ml) in 40.7%, decreased in 29.6%, unchanged in 18.5%, and increased in 11.1%, which was almost parallel to the GH changes. Conclusions. Gamma knife surgery was effective and safe for the control of tumors; however, normalization of GH and IGF-1 secretion was difficult to achieve in cases with large tumors and low-dose radiation. Gamma knife radiosurgery is thus indicated for small tumors after surgery or medication therapy when a relatively high-dose radiation is required.

scholarly journals Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

2000 ◽  
Vol 167 (2) ◽  
pp. 295-303 ◽  
Author(s):  
JW van Neck ◽  
NF Dits ◽  
V Cingel ◽  
IA Hoppenbrouwers ◽  
SL Drop ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Receptor Antagonist ◽  
Growth Hormone Receptor ◽  
Binding Protein ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Gh Receptor ◽  
Igf I ◽  
Igfbp 3

The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.

Differential effects of octreotide treatment and transsphenoidal surgery on growth hormone—binding protein levels in patients with acromegaly

1999 ◽  
Vol 90 (4) ◽  
pp. 647-650 ◽  
Author(s):  
Irma Hernandez ◽  
Daniela Soderlund ◽  
Ana Laura Espinosa-de-los-Monteros ◽  
Raquel Ochoa ◽  
Arturo Zarate ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Transsphenoidal Surgery ◽  
Binding Protein ◽  
Hormone Binding ◽  
Content Type ◽  
Growth Hormone Binding Protein ◽  
Igf I ◽  
Octreotide Treatment ◽  
Hormone Binding Protein ◽  
Fine Print

Object. The high-affinity growth hormone—binding protein (GHBP) represents the extracellular portion of the growth hormone (GH) receptor, and its serum levels are a reflection of the tissue receptor status. Levels of GHBP are decreased in patients with active acromegaly, probably because of downregulation of GH receptors. However, there are no studies of patients with acromegaly in which the effects of medical (that is, administration of somatostatin analogs) and surgical therapy on GHBP levels have been compared. That is the task the authors set out to accomplish in this study.Methods. The authors studied seven patients in whom acromegaly had been recently diagnosed. They examined these patients at baseline, 2 months after octreotide treatment (subcutaneous administration of 100 µg octreotide three times per day), and 1 month after transsphenoidal surgery. Growth hormone—binding activity was measured, as well as the following biochemical markers of the somatotropic axis: GH suppression induced by oral administration of glucose, insulin-like growth factor-I (IGF-I), and insulin-like growth factor—binding protein-3 (IGFBP3). Although octreotide treatment induced a decrease in the levels of GH, IGF-I, and IGFBP3, as well as an increase in the level of GHBP, these biochemical markers did not reach normal levels. On the other hand, after transsphenoidal surgery, GHBP levels became normal, particularly in those patients in whom serum GH could be suppressed to an undetectable level after glucose loading.Conclusions. The authors conclude that persistently low GHBP levels in patients with acromegaly are normalized by successful pituitary surgery and correlate well with disease activity.

In vivo assessment of the window of barrier opening after osmotic blood—brain barrier disruption in humans

2000 ◽  
Vol 92 (4) ◽  
pp. 599-605 ◽  
Author(s):  
Tali Siegal ◽  
Rina Rubinstein ◽  
Felix Bokstein ◽  
Allan Schwartz ◽  
Alexander Lossos ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Time Course ◽  
Photon Emission ◽  
Brain Barrier ◽  
Therapeutic Window ◽  
Content Type ◽  
Blood Brain ◽  
The Mean ◽  
Fine Print

Object. Osmotic blood—brain barrier (BBB) disruption induced by intraarterial infusion of mannitol is used in conjunction with chemotherapy to treat human brain tumors. The time course to barrier closure, or the so-called therapeutic window, has been examined in animals but little information is available in humans. The authors, therefore assessed the time course to barrier closure after osmotic BBB disruption in humans.Methods. Disruption of the BBB was demonstrated using 99mTc-glucoheptonate (TcGH) single-photon emission computerized tomography (SPECT) scanning in 12 patients who were treated monthly with combination chemotherapy in conjunction with BBB disruption. The primary diagnosis was primary central nervous system lymphoma in seven patients and primitive neuroectodermal tumors in five. The TcGH (20 mCi) was injected at 1- to 480-minute intervals after osmotic BBB disruption, and patients underwent SPECT scanning after 4 hours. A total of 38 studies was performed. Good-to-excellent BBB disruption was obtained in 29 procedures and poor-to-moderate disruption was seen in the other nine studies.The TcGH indices correlated with the degree of BBB disruption as measured postprocedure on contrast-enhanced CT scans (r = 0.852). Mean baseline TcGH indices were 1.02 ± 0.07. For the group of patients with good-to-excellent disruptions the mean indices at 1 minute postdisruption measured 2.19 ± 0.18. After 40 minutes no significant change was noted (mean index 2.13 ± 0.2). Then the indices declined more steeply and at 120 minutes after the disruption the index was 1.36 ± 0.02. A very slow decline was noted between 120 and 240 minutes after mannitol infusion. At 240 minutes the barrier was still open for all good-to-excellent disruptions (index 1.33 ± 0.08) but at 480 minutes the mean indices had returned to the baseline level.Conclusions. Results of these in vivo human studies indicate that the time course to closure of the disrupted BBB for low-molecular-weight complexes is longer than previously estimated. The barrier is widely open during the first 40 minutes after osmotic BBB disruption and returns to baseline levels only after 6 to 8 hours following the induction of good or excellent disruption. These findings have important clinical implications for the design of therapeutic protocols.

Volume reduction in meningiomas after gamma knife surgery

2005 ◽  
Vol 102 ◽  
pp. 189-194 ◽  
Author(s):  
Guenther C. Feigl ◽  
Otto Bundschuh ◽  
Alireza Gharabaghi ◽  
Madjid Samii ◽  
Gerhard A. Horstmann
Keyword(s):  
Gamma Knife ◽  
Tumor Volume ◽  
Gamma Knife Surgery ◽  
Volume Reduction ◽  
World Health ◽  
Tumor Control ◽  
Content Type ◽  
The Mean ◽  
Fine Print

Object.The purpose of this study was to evaluate the volume-reducing effects of gamma knife surgery (GKS) of meningiomas with and without previous surgical treatment.Methods.A group of 127 patients with a mean age of 57.1 years (range 9–81 years) with 142 meningiomas (128 World Health Organization Grade I and 14 Grade II) were included in this study. The management strategy reduces tumor volume with surgery when necessary (81 patients). Stereotactic GKS with a Gamma Knife model C was performed in all tumors of suitable size. Magnetic resonance imaging follow-up examinations with volumetric tumor analysis was performed 6 months after treatment and annually thereafter.The mean tumor volume was 5.9 cm3(range < 5 to > 40 cm3). The mean follow-up time after GKS was 29.3 months (range 11–61 months). The mean prescription dose was 13.8 Gy (range 10–18 Gy). A reduction in volume occurred in 117 (82.4%) of all tumors, and in 20 tumors (14.1%) growth ceased. The overall tumor control rate of 96.4%. The mean volume reduction achieved with GKS was more than 46.1%. Only five tumors (3.5%) showed a volume increase.Conclusions.Gamma knife surgery was effective in reducing meningioma volume at short-term follow up. Further studies are needed to examine the development of these findings over a longer period.

Evaluation of a new concept for the management of skull base chordomas and chondrosarcomas

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 165-170 ◽  
Author(s):  
Guenther Christian Feigl ◽  
Otto Bundschuh ◽  
Alireza Gharabaghi ◽  
Sam Safavi-Abassi ◽  
Amr El Shawarby ◽  
...  
Keyword(s):  
Skull Base ◽  
Tumor Volume ◽  
Tumor Resection ◽  
Volume Reduction ◽  
Recurrence Rates ◽  
Content Type ◽  
The Mean ◽  
Tumor Volume Reduction ◽  
Fine Print

Object. Chordomas and chondrosarcomas of the skull base are rare locally invasive tumors associated with high recurrence rates. The aim of this study was to evaluate the concept of microsurgical tumor volume reduction followed by early gamma knife surgery (GKS). Methods. Thirteen patients with 15 tumors were treated between October 2000 and June 2003. There were three patients (23.1%) with chordomas and 10 (76.9%) with chondrosarcomas. There were nine men and four women who ranged in age between 19 and 69 years. All patients first underwent maximal tumor resection. Within 2 to 10 months after surgery they were treated with GKS. The mean postoperative tumor volume treated with GKS was 9.7 cm3 (range 1.4–20.3 cm3). Follow-up computerized tomography and magnetic resonance imaging examinations with volumetric tumor analysis were performed every 6 months after GKS. The mean treatment dose was 17 Gy and the mean isodose was 52%. The mean follow-up duration was 17 months during which there was only one tumor recurrence at the margin of the radiation field. The mean volume reduction was 35.4%. Conclusions. Results of this treatment strategy are encouraging but the efficacy of this multimodal treatment combining surgery and early GKS requires a longer follow up.

scholarly journals Growth Hormone Signaling in Vivo in Human Muscle and Adipose Tissue: Impact of Insulin, Substrate Background, and Growth Hormone Receptor Blockade

2008 ◽  
Vol 93 (7) ◽  
pp. 2842-2850 ◽  
Author(s):  
Charlotte Nielsen ◽  
Lars C. Gormsen ◽  
Niels Jessen ◽  
Steen Bønløkke Pedersen ◽  
Niels Møller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Signaling Pathways ◽  
Cross Talk ◽  
Insulin Signaling ◽  
Human Muscle ◽  
Receptor Blockade ◽  
Gh Receptor ◽  
Igf I

Abstract Context: GH induces insulin resistance in muscle and fat, and in vitro data indicate that this may involve cross-talk between the signaling pathways of the two hormones. Objective: Our objective was to investigate GH and insulin signaling in vivo in human muscle and fat tissue in response to GH, GH receptor blockade, and insulin stimulation. Design: We conducted two randomized crossover studies. Participants: Sixteen healthy males participated. Intervention: GH was administered as a bolus (n = 8) and constant infusion (n = 8). The bolus study included three arms: 1) control (saline), 2) GH (0.5 mg iv), and 3) GH blockade (pegvisomant 30 mg sc), each combined with a hyperinsulinemic glucose clamp. The infusion study included two arms: 1) GH infusion (45 ng/·kg·min, 5.5 h) and 2) saline infusion (5.5 h) combined with a hyperinsulinemic glucose clamp during the final 2.5 h. Main Outcome Measures: Muscle and fat biopsies were subjected to Western blotting for expression of Stat5/p-Stat5, Akt/p-Akt, and ERK1/2/p-ERK1/2 and to real-time RT-PCR for expression of SOCS1–3 and IGF-I mRNA. Results: GH significantly reduced insulin sensitivity. The GH bolus as well as GH infusion induced phosphorylation of Stat5 in muscle and fat, and SOCS3 and IGF-I mRNA expression increased after GH infusion. Hyperinsulinemia induced Akt phosphorylation in both tissues, irrespective of GH status. In muscle, ERK1/2 phosphorylation was increased by insulin, but insulin per se did not induce phosphorylation of Stat5. Conclusions: GH exposure associated with insulin resistance acutely translates into GH receptor signaling in human muscle and fat without evidence of cross-talk with insulin signaling pathways. The molecular mechanisms subserving GH-induced insulin resistance in humans remain unclarified.

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