Growth Hormone Receptor Antagonists

Alex F. Muller, John J. Kopchick, Allan Flyvbjerg and Aart Jan van der Lely

Department of Internal Medicine, Diakonessenhuis Utrecht (A.F.M.), 3582 KE Utrecht, The Netherlands; Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University (J.J.K.), Athens, Ohio 45701; Medical Department M/Medical Research Laboratory, Institute of Experimental Clinical Research, Aarhus Kommunehospital, University of Aarhus (A.F.), DK 8000 Aarhus, Denmark; and Department of Endocrinology, Erasmus University Medical Center (A.J.v.d.L.), 3015 GD Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Alex F. Muller, M.D., Department of Internal Medicine, Diakonessenhuis Utrecht, Bosboomstraat 1, 3582 KE Utrecht, The Netherlands. E-mail: amuller{at}diakhuis.nl.


    Introduction
 Top
 Introduction
 References
 
Pegvisomant is the only member of a new class of drugs that was especially designed to block the GH receptor (GHR) and, therefore, GH action. In this review we will describe the structure and function of GH and its receptor with specific relevance to the discovery and development of GHR antagonists. With respect to clinical applications, we will first discuss the role of pegvisomant in the treatment of acromegaly. Thereafter, the potential role that pegvisomant might play in the treatment and prevention of late complications of diabetes mellitus and cancer will be discussed and compared with those of somatostatin analogs in these settings.

Rationale for GHR antagonists

GH is secreted by the somatotrophs of the anterior pituitary gland and acts on various tissues to promote growth and influence metabolism (1, 2). GH signal transduction begins with GH binding to a GHR on the plasma membrane (3). The cocrystal structure of the GH-GHR complex indicates that GH interacts with a preformed GHR dimer. This interaction is critical for GH-induced intracellular signal transduction (4). GH has two distinct domains (sites 1 and 2) that bind to the two identical GHRs at the cell surface. After initial, high affinity binding at site I, subsequent binding at site 2 produces functional receptor dimerization (Fig. 1AGo). After the GH/GHR interaction, a series of intracellular signaling systems are mobilized, ultimately resulting in the activation or inactivation of genes that are responsible for GH phenotypic effects (5). In humans and most mammals, the extracellular part of the GHR can be released from the cell surface by proteolytic cleavage, resulting in the generation of a serum GH-binding protein (6).



View larger version (44K):
[in this window]
[in a new window]
 
FIG. 1. A, Signaltransduction pathway of normal GH using two identical transmembrane GHRs. B, Lack of signal transduction after binding of pegvisomant with the two identical transmembrane receptors, leading to nonfunctioning dimerization.

 
Structure of GH

GH is a protein that contains 191 amino acids with two disulfide bonds and four {alpha}-helixes (4, 7). Its molecular mass is approximately 22,000 Da. The structure of GH has been determined by x-ray crystallography (4, 7). Structure-function studies have determined specific regions of the molecule to be important for GHR binding (4, 8).

Discovery of a GH antagonist

In the late 1980s, Chen et al. (9) observed that the amino acids in the third {alpha}-helix of GH are arranged in such a way that one half of the helix is hydrophobic, and the other half is hydrophilic (i.e. in an amphipathic configuration). They noted that the amino acids at positions 117, 119, and 122 prevent the formation of a perfect amphiphilic helix. Also, it had been shown previously that a peptide containing the third {alpha}-helix of GH possessed low, but significant, growth-promoting activity (10). Therefore, it was assumed that the generation of a perfect amphipathic helix 3 would result in a GH analog with enhanced biological activity. Surprisingly, transgenic mice that expressed such a GH analog with a perfect amphipathic helix 3 (bGH-M8) possessed decreased circulating IGF-I levels and exhibited a dwarf phenotype (9, 11). The observed dwarf mouse phenotype and the fact that bGH-M8 inhibited binding of [125I]bGH to liver membrane preparations resulted in the first report of a GHR antagonist (9, 11).

Subsequently GH analogs with single amino acid substitutions at positions 117, 119, and 122 were generated to examine which of the residues were critical for GH action. These studies revealed that glycine at position 119 was, in fact, critical for the growth-promoting activity. Similar studies with a human GH (hGH) analog, in which the corresponding critical amino acid is glycine 120, have yielded similar results (12, 13).

Chen et al. (12) proposed that the GHR antagonist interacted correctly with the GHR,but the antagonistic properties were due to the inability to interact with a second target protein. This second target protein was later identified by de Vos et al. (4) to be a second GHR. Together, these data suggested that the mechanism by which the GHR antagonist acts is by failing to induce proper or functional GHR dimerization (Fig. 1BGo). Thus, by combining site-specific mutagenesis studies of the GH gene with the in vivo assay of the ability of GH analogs to regulate the growth of transgenic mice, a GHR antagonist was discovered (11, 12, 14, 15, 16, 17). This discovery set the stage for the development of the GHR antagonist for clinical use.

Pegvisomant

The potential use of a GHR antagonist for clinical indications resulting from elevated levels of GH, such as acromegaly, or those in which GH or IGF-I may play a pathophysiological role was immediately recognized.

Like GH, the GHR antagonist possesses a relatively small size (i.e. ~22 kDa). GH has a half-life of approximately 15 min and is normally cleared via the kidneys and/or GHR internalization (18). To enhance the half-life of the GHR antagonist, several polyethylene glycol (PEG) molecules were added to the molecule. These additions increased the size of the antagonist and also increased the serum half-life from approximately 30 min to more than 100 h (19).

Also, Cunningham et al. (20) have defined eight amino acid residues in GH that, when altered, increased the binding affinity of GH site 1 to the GHR. A molecule containing nine amino acid substitutions (the original substitution of glycine 120 as well as eight mutations in site 1) was produced and combined with PEG. The resulting molecule, known as PEG-hGH G120K (B2036 peg), was shown to maintain its GHR binding and antagonistic properties (see Fig. 1Go) (21). PEG-hGH G120K (with pegvisomant as the generic name) is currently available in the U.S. for the treatment of acromegaly. Its trade name is Somavert (22). The European commission has approved the use of pegvisomant for acromegaly in Europe, and it will most likely soon be available for clinical use in most European countries.

Mechanism of action

After GH binding to the GHR, the complex is internalized (18, 23, 24, 25, 26, 27, 28, 29). Surprisingly, both pegvisomant and the non-pegylated GHR antagonist binds to the GHR with approximately the same affinity as GH, form dimers, and are internalized (26, 27, 28). It was argued that the GHR antagonist with eight amino acid substitutions in GH site 1 would result in molecules that would bind to the GHR with increased affinity. However, of the eight amino acid changes made within binding site 1, two (namely lysine to alanine and lysine to arginine at positions 168 and 172, respectively) are critical for site 1 binding to the GHR. Pegylation of these residues in the native molecule would block or sterically hinder binding of the antagonist to the first GHR. Thus, substitution of these residues removes potential pegylation sites within binding site 1 and, thus, ensures that site 1 of pegvisomant remains accessible to the GHR (15, 28).

Clinical development

Pegvisomant in the treatment of acromegaly. Acromegaly is usually caused by a benign GH-secreting pituitary adenoma and is associated with an increased mortality rate (30, 31, 32). Currently available treatment modalities consist of surgery, radiotherapy, and medication. Unfortunately, surgery cures only approximately 60% of patients. Also, less than half of the patients with macroadenomas (which constitute the majority of patients with acromegaly) are cured via surgery (33, 34). The effect of radiotherapy is delayed and variable, with a high incidence of late panhypopituitarism (35, 36, 37, 38, 39, 40, 41, 42). Available medical treatment modalities are dopamine agonists (bromocriptine, quinagolide, and cabergoline) and somatostatin analogs (octreotide and lanreotide). Dopamine agonists have limited efficacy and tolerability and are, in general, less effective than the somatostatin analogs (43, 44). Long-acting somatostatin analogs are given every 2–4 wk and normalize serum IGF-I levels in about 65% of patients (45, 46, 47, 48). This still leaves at least one third of patients eligible for a more effective medical therapy. In 2000, Herman-Bonert et al. (49) reported six patients with macroadenomas, four with cavernous sinus extension, who were resistant to maximal doses of octreotide therapy and who normalized their IGF-I levels while receiving short-term therapy with pegvisomant.

Two important studies have tried to establish the efficacy of long-term pegvisomant therapy in the treatment of acromegaly (50, 51). In a double-blind placebo controlled study, 112 patients with active acromegaly were treated for 12 wk with either placebo or one of three sc dosages (10, 15, or 20 mg) of pegvisomant (51). Parameters monitored during this study were serum IGF-I and GH concentrations as well as a questionnaire evaluating soft tissue swelling, arthralgia, headache, excessive perspiration, and fatigue. In pegvisomant-treated patients, a dose-related improvement in symptoms and signs was observed. Serum IGF-I concentrations decreased significantly in all treatment groups, and 82% of patients treated with the highest dose achieved normal serum IGF-I concentrations by the end of the study. Although pegvisomant seemed a very effective drug for the treatment of acromegaly, questions concerning safety and efficacy over the long term remained (52).

To address these questions, the study was extended to include 152 patients who were treated for up to 18 months (50). Pegvisomant was administered by daily sc injection and titrated until the serum IGF-I level became normal or a maximum dose of 40 mg was reached. Of patients treated for 12 months, 97% (i.e. 87 of 90) achieved normal IGF-I levels (Fig. 2Go) (50).



View larger version (14K):
[in this window]
[in a new window]
 
FIG. 2. Serum concentrations of IGF-I (•) in patients who completed at least 6 months (n = 131), 12 months (n = 90), or 18 months (n = 39) of daily pegvisomant treatment. The cohorts are sequentially constructed, such that all patients in the 18-month treatment cohort were also included in the 6- and 12-month cohorts, and the patients in the 12-month cohort were also included in the 6-month cohort. For all cohorts, the baseline visit was considered the visit immediately before beginning pegvisomant therapy in the initial study protocol. Baseline values were calculated using only data from patients in each cohort. All changes from baseline were statistically significant (P < 0.05) for all cohorts. Data are reprinted with permission (50 ).

 
During long-term pegvisomant therapy, GH levels increased substantially. This could be indicative of an increase in pituitary tumor size (52, 53). For 131 patients with adenomas of more than 1 cm3, paired sets of baseline and follow-up scans (mean time between scans, 11.46 months) did not show a significant increase in tumor volume (50). But two patients (of 149 for whom baseline magnetic resonance imaging scans were available), who were not pretreated with radiotherapy, demonstrated a clinically significant increase in tumor size (50). Interestingly, in one of these patients cotreatment with octreotide halted further tumor growth and resulted in a synergistic decrease in serum IGF-I concentrations (54). Another two patients developed a significant, but reversible, increase in serum liver enzyme concentrations in the first 3 months after starting pegvisomant treatment. One of these patients was rechallenged, and liver enzymes rose again (50), proving a causal relation. Thus liver enzymes should be followed when pegvisomant is used. In conclusion, pegvisomant is the most effective treatment for normalizing IGF-I in acromegaly. Pegvisomant administered for 1 yr appears to be safe, although in two patients who had not received radiotherapy before pegvisomant treatment, a clinically significant increase in tumor size was observed. Also, in two patients, pegvisomant induced liver function disturbances. Therefore, patients receiving pegvisomant should have adenoma size assessed by magnetic resonance imaging once a year (55). In addition, pegvisomant should not be prescribed to patients who have clearly abnormal liver function. Patients who are treated should be monitored for liver function tests once a month during the first 6 months of treatment (55). Clearly, there is an urgent need for a long-term follow-up program for all patients treated with pegvisomant to detect adverse effects and be able to improve current treatment recommendations. Finally, it should be emphasized that no comparative studies between pegvisomant and somatostatin analogs have been performed to date.

Effects of GH receptor antagonists in diabetes mellitus. The first association between GH and diabetes was presented by Young (56) in 1937, showing that administration of anterior pituitary extracts to dogs resulted in diabetes. This result was confirmed and expanded by Campbell et al. (57), who showed that daily injections of highly purified GH made dogs permanently diabetic. The interest in GH and diabetes was facilitated 30 yr ago when it was shown that diabetic patients present with GH hypersecretion (58, 59). At the same time the GH hypothesis was launched, suggesting that GH plays an important role in the development of diabetic microangiopathy (i.e. retinopathy) (60).

The role of IGFs in diabetes appears to be much shorter, although 30 yr ago low levels of the so-called sulfation factor or nonsuppressible insulin-like activity were reported in diabetic patients (61). Today it is generally believed that the metabolic deterioration in diabetes first decreases hepatic IGF-I formation and serum IGF-I levels, which then secondarily induces GH hypersecretion through an intact feedback mechanism (62, 63, 64). Increased circulating GH concentrations are then believed to stimulate local IGF-I concentrations in nonhepatic tissues. With respect to the kidney, there are strong data to support such a mechanism. In a study in which diabetic mice were treated with either a placebo or a GHR antagonist, it was shown that liver IGF-I levels were low, and kidney IGF-I levels were elevated. Interestingly, in the GHR antagonist-treated mice, serum IGF-I levels were unchanged, whereas kidney IGF-I levels were normalized (65). However, there are no such data on the effect of GHR antagonist treatment on local IGF-I production in other nonhepatic tissues (in the context of this manuscript, most notably retina and vascular tree).

The expected benefit of suppressing increased circulating GH levels to minimize the deleterious effects on diabetic metabolic aberration and prevention of development of long-term diabetic complications have facilitated the investigation of inhibitors of the GH system for the use in diabetes. In this context, both GHR antagonists and somatostatin analogs are interesting candidates for preventing long-term diabetic complications.

Nephropathy. It is well established that in various experimental models of type 1 diabetes, GH and IGFs have measurable effects on both short- and long-term renal changes (62, 63, 65, 66, 67). Several studies have investigated the effects of somatostatin analogs on renal changes. Initial renal hypertrophy in streptozotocin-induced diabetic rats can be prevented by administration of a long-acting somatostatin analog (Sandostatin) (68). In another study, the long-term effects of somatostatin analog administration in streptozotocin-induced diabetic and nondiabetic rats were investigated (69). In the somatostatin analog-treated animals, kidney weight and urinary albumin excretion (UAE) were reduced compared with those in untreated diabetic animals (69). In the nonobese diabetic (NOD) mouse, another animal model of type 1 diabetes, similar results were obtained (70). A standard treatment for diabetic nephropathy consists of angiotensin-converting enzyme inhibitors (ACEi). Gronback et al. (71) have investigated treatment with a somatostatin analog and ACEi alone and compared the effects to those of insulin treatment. Insulin treatment resulting in euglycemia nearly normalizes renal and glomerular growth and UAE. Treatment with a somatostatin analog and ACEi, alone and in combination, reduced renal, but not glomerular, size. Also, only the combination of drugs reduced UAE as well (71).

The hypothesis that GHR antagonists may be used in the treatment of diabetic renal changes was supported by long-term studies in streptozotocin-induced diabetic mice transgenic for a GHR antagonist. These animals were protected against the development of diabetic renal changes (72, 73). These beneficial inhibitory effects of the GHR antagonist in transgenic mice were seen without alterations in glycemic control. These results were further supported by data obtained in a study in streptozotocin-induced diabetic, GHR gene-disrupted mice. These mice were also protected against diabetes-induced renal changes (74).

To elucidate the potential usefulness of GHR antagonists as therapeutic agents in diabetic kidney disease, a series of studies with exogenous administration of a GHR antagonist to diabetic mice were recently conducted (65, 75). In GHR antagonist-treated, streptozotocin-induced diabetic mice, glomerular hypertrophy, renal enlargement, and renal IGF-I accumulation were abolished, and the diabetes-associated increase in UAE was reduced (Fig. 3Go) (65). These effects were achieved through a specific mechanism at the renal GHR level, as no effect of treatment was seen on metabolic control, including serum GH and IGF-I levels (65). Also, in another model of type 1 diabetes, the NOD mouse, exogenous administration of a GHR antagonist attenuated kidney weight compared with that in nontreated controls. Glomerular hypertrophy and UAE were increased in nontreated diabetic mice (as expected), but were similar to those in nonhyperglycemic littermates in GHR antagonist-treated mice (75). Recently, the effect of the GHR antagonist, alone or in combination with administration of an ACEi, was examined on renal changes in NOD mice (76). Preliminary results showed that GHR antagonist treatment was equally potent to ACEi treatment in reducing UAE (76).



View larger version (39K):
[in this window]
[in a new window]
 
FIG. 3. Inhibitory effect of a GHR antagonist (G120K-PEG) on diabetes-induced glomerular hypertrophy and rise in UAE in nondiabetic mice treated with placebo (CP) or GHR antagonist (CA) and in diabetic mice treated with placebo (DP) or GHR antagonist (DA). Values are means ± SE. *, P< 0.05 vs. all other groups (CP, CA, and DA). {Delta}, P< 0.05 vs. all other groups (CP, CA, and DP). ©1999 American Diabetes Association. From Diabetes 48:377–382 (65 ). Reprinted with permission from The American Diabetes Association.

 
Somatostatin analogs, but not GHR antagonists, have been studied in patients with type 1 diabetes. In 11 patients with type 1 diabetes and glomerular hyperfiltration, sc administration of the somatostatin analog octreotide reduced glomerular filtration rate and kidney size, whereas glycemic control remained unchanged (77). However, in another study in which four patients with type 1 diabetes were treated for 9 months with a long-acting somatostatin analog, increased renal plasma flow and glomerular filtration rate were only temporary reduced (78).

In conclusion, in different animal models of type 1 diabetes mellitus, both somatostatin analogs and GHR antagonists have favorable effects on diabetes-induced renal changes. Considering the different hormonal profiles of somatostatin analogs and GHR antagonists (low GH and IGF-I vs. high GH and low IGF-I, respectively), these renal effects are remarkably similar and occur without changes in the level of glycemic control. However, to date, the effects of GHR antagonists in animal models of type 2 diabetes have not been reported. Moreover, human studies investigating the renal effects of GHR blockade in diabetes mellitus (type 1 or 2) have not been performed. Taking into account the prevalence of diabetes and the fact that somatostatin analogs only led to a temporary improvement in UAE in humans with type 1 diabetes, we believe that further studies of the potential beneficial effects of GHR antagonists in diabetic nephropathy are warranted.

Retinopathy. A possible role of GH in the pathogenesis of diabetic retinopathy was originally suggested by the observation of regressing proliferative diabetic retinopathy after pituitary ablation (79, 80). Since then, various studies have investigated the use of somatostatin analogs for diabetes-induced proliferative retinopathy (81, 82, 83, 84). Collectively, these studies suggest that somatostatin analogs retard the progression of advanced stages of diabetic retinopathy and decrease the need for vitroretinal surgery.

Only a few studies have appeared on the impact of GHR blockade on the development of retinopathy. The role of GH in nondiabetic, ischemia-associated, retinal neovascularization has been studied in transgenic mice expressing a GHR antagonist. In this study, retinal neovascularization was inhibited despite an elevation of vascular endothelial growth factor receptor expression (85). However, in a recent clinical study, 25 diabetic patients (13 type 1 and 12 type 2 diabetics) with proliferative retinopathy were treated with pegvisomant for 12 wk (86). Despite a 55% reduction in serum IGF-I, 16 patients had an unchanged degree of retinopathy, and nine patients showed progression (86). Accordingly, these results do not support a beneficial effect of pegvisomant on diabetic retinopathy.

This failure to achieve an improvement in the degree of retinopathy is disturbing and needs further clarification. Relevant human data (reviewed in Ref. 84) indicate that somatostatin is produced locally in the retina. As, somatostatin receptors are also expressed in the human retina, with somatostatin receptor subtype 2 being the most widely expressed, these data may indicate an autocrine action of somatostatin in the human retina (84). Recently, Simó et al. (87) have presented data indicating a significantly impaired intraocular production of somatostatin. By hypothesizing that somatostatin receptor subtype 2-specific somatostatin analogs compensate for the impaired intraocular production of somatostatin and can bind to the somatostatin receptors present in the human retina, these data can provide an explanation for why somatostatin analogs, but not GHR antagonists, can retard the progression of advanced stages of diabetic retinopathy.

Before discarding GHR antagonists as a possible treatment for diabetic retinopathy, however, it would be relevant to study larger groups of type 1 and type 2 diabetic patients, treated for a longer period than 12 wk. Also, it would be of interest to study patients with less severe diabetic eye disease than those examined in the study described above.

Metabolism. Due to the well-known diabetogenic effect of GH, GH hypersecretion has been suggested to contribute to a deterioration of metabolic control in diabetic subjects. Theoretically, administration of pegvisomant to diabetic subjects may either improve metabolic control, by blocking the diabetogenic effects of GH, or deteriorate metabolic control by further lowering circulating IGF-I. However, in the experimental studies performed in GHR antagonist transgenic mice (72, 73) or mice treated with a GHR antagonist (65, 75), no glycemic effect was noted. Furthermore, in a recent study of healthy subjects, the effect of pegvisomant on carbohydrate metabolism was studied and compared with the effect of a long-acting somatostatin analog (octreotide). Pegvisomant, unlike octreotide, was not associated with deterioration in glucose tolerance (88).

In conclusion, experimental data suggest that GHR blockade, by the use of GHR antagonists, may present a new concept in the treatment of diabetic renal complications. However, to date there have been no human data showing beneficial effects; therefore, future studies are warranted to delineate the potential of GHR antagonists as possible drugs for the treatment of diabetic complications.

Potential use of GHR antagonists in cancer

The importance of the GH/IGF-I axis in oncology is probably best divided into two major categories: tumorigenesis and tumor growth. Regarding tumorigenesis, one preclinical study has been reported that examines the impact of manipulating the GH/IGF-I hormonal milieu with a GHR antagonist (89). In this study the tumor incidence rate was measured in transgenic mice expressing a GHR antagonist and in control littermates after exposure to dimethylbenz[a]anthracene, a mammary gland carcinogen. The transgenic animals were significantly smaller and had significantly lower IGF-I concentrations. The transgenic animals also exhibited decreased tumor incidence relative to controls (68.2 vs. 31.6% tumor free at 39 wk) (89). These data are interesting, as a series of epidemiological analyses have linked circulating IGF-I concentrations or IGF-I/IGF-binding protein 3 ratios (as an indirect measure of free IGF-I) with the risk of developing prostate, breast, and colon cancer (89, 90, 91, 92).

With respect to modulating tumor growth once neoplastic transformation has occurred, numerous preclinical studies have defined IGF-I as potent growth factor for many different tumor types. This work, performed over several decades, has been assembled into a comprehensive review (93). What is clear from this extensive series of experiments is that there are many levels of action through which the GH/IGF-I axis may influence the growth of a particular type of neoplasm. These range from blocking the direct actions on GHRs present in the tumor to decreasing the amounts of autocrine, paracrine, or endocrine IGF-I available to stimulate tumor growth. In some cases, even IGF-II, acting via the IGF-I receptor, can stimulate growth (94, 95). Besides the GHR antagonist, a number of other agents are also capable of manipulating the GH/IGF-I hormonal milieu. These include GHRH antagonists, somatostatin analogs, IGF-I receptor antibody, IGF-I/II antisense vector strategies, and IGF-binding proteins (93). Some of the potential paths of GH and IGF-I/II influence on tumor growth are outlined in Fig. 4Go.



View larger version (15K):
[in this window]
[in a new window]
 
FIG. 4. Mechanisms through which the GH/IGF-I axis may influence the growth of a neoplasm.

 
There have been several experiments that have specifically examined the ability of GHR antagonists to modify tumor growth. Most of this work has been performed using xenograft or syngenic models in mice. Effects on several different tumor types have been reported. Below, we will compare the effects of the GHR antagonists with those of somatostatin analogs (as these compounds are currently available for manipulating the GH/IGF-I hormonal milieu).

Because in vitro IGF-I has been demonstrated to be a potent growth factor for primary cultures of human meningioma specimens, the effect of pegvisomant was studied in more detail in an in vivo tumor model (96). Primary cultures from 15 meningioma tumors obtained from humans were xenografted into pairs of athymic mice. One animal from each of the 15 pairs was then treated with pegvisomant, and the other was treated with vehicle. After 8 wk, the mean tumor volume in the pegvisomant group was 57% compared with that in controls. Circulating IGF-I concentrations in the treatment group were 81% of those in the vehicle group (97). Somatostatin receptors are present on 96% of human meningeomas (98). Surprisingly, both somatostatin and its analog, octreotide, resulted in a slight, but significant, stimulation of human meningeoma cells in vitro (99). Therefore, somatostatin analogs seem less attractive in the treatment of inoperable meningeomas.

Although controversial, colonic cancer has been reported to occur with increased frequency in patients with acromegaly (100). Several experiments using both somatostatin analogs and pegvisomant have been performed using a variety of colon cancer models. Somatostatin analogs have been shown to reduce the growth of several colonic cancer cell lines in vivo (101, 102, 103, 104). Also, treatment with a somatostatin analog was able to reduce the incidence and number of hepatic metastasis after intrasplenic tumor injection (105). In one preliminary study pegvisomant was shown to reduced the volume and weight of xenografted COLO 205 tumors by 39 and 44%, respectively, compared with untreated animals (106). In a model designed to look at colon cancer hepatic metastases, pegvisomant showed some promising results. Interestingly, the combination of pegvisomant and the commonly used topoisomerase 1 inhibitor, irinotecan, was superior to either therapy alone. Beneficial effects on the size of the primary tumor and the size/number of hepatic metastases were observed (107).

Somatostatin analog, but not pegvisomant, treatment has been investigated in several clinical studies (108, 109, 110, 111). In one of these studies involving subjects with advanced colon carcinoma refractory to chemotherapy, patients treated with octreotide had a significant advantage in duration of survival, with a median survival time of 20 vs. 11 wk in the control group (P < 0.0001). However, in the largest study to date, no survival benefit was observed (111).

In breast tumors, IGF-I receptor expression is nearly ubiquitous, and receptor activation is thought to be the growth stimulus (93). IGF-I and IGF-II produced by mammary stromal elements may stimulate growth of the malignant breast tissue (93). Several researchers have suggested a positive correlation between serum IGF-I levels and the risk of breast cancer (91, 112). Unfortunately, in none of the clinical studies performed did treatment with somatostatin analogs, either alone or combined with tamoxifen, result in favorable outcomes (113, 114, 115, 116, 117). Therefore, other means of targeting IGF-I-mediated growth have been sought. Preliminary data show that pegvisomant reduces the growth of several breast cancer cell lines, including both estrogen receptor-positive and -negative representatives, by 42–62% of that observed in control animals (118). Before more definitive statements can be made with regard to the potential utility of pegvisomant in the treatment of breast cancer, more experimental and clinical data are needed.

In addition to heterogeneity in tumors and tumor types, there is likely to be a significant difference in how normal tissues respond to agents such as GHR antagonists. For instance, it is well known that GH directs much of the IGF-I production in the liver. IGF-I production in some other tissues, however, is not necessarily regulated predominately by GH. Also, TSH is a major stimulus of IGF-I production in the thyroid (119), and estrogen is the primary stimulus in the endometrium (120). A GHR antagonist would not necessarily be effective in down-regulating IGF-I production by those tissues if it needs to act locally at the tissue level.

One intriguing possibility for the use of pegvisomant is in combination with other agents. For instance, experimental data have identified IGF-I as a potent agent with respect to inhibiting apoptosis (121). By lowering IGF-I in the microenvironment around a tumor, it could be possible to obtain a better response to a cytotoxic insult delivered by a traditional chemotherapeutic agent. IGF-I has also been demonstrated to stimulate angiogenesis (122). Therefore, therapy with an agent designed to target the endothelial cell proliferation that supports tumor growth might be of potential benefit.

In conclusion, currently there are challenging, albeit highly experimental, data to support a role for GHR antagonists in the treatment of cancer. However, because IGF-I seems to be a growth factor for some cell lines, and somatostatin analogs exhibit some measurable activity in most tumors investigated (123), the concept of modulating tumor growth by inhibiting the GH/IGF-I axis still seems worthwhile. In this respect it should be noted that, to date, most series investigating the use of somatostatin analogs in oncology have been performed in a nonrandomized approach in patients with highly disseminated disease, who had also been pretreated in the majority of studies, thus introducing a negative bias (123). Therefore, we believe that further investigations are in order. Establishing the GHR status of the tumor, assessment of optimal combination of pegvisomant with chemotherapeutic agents, and other hormonal therapy (even combination with somatostatin analogs) should be considered. Clearly, as such studies are ongoing, it is important to couple the disciplines of endocrinology and oncology to achieve the greatest likelihood of success.

Summary

Pegvisomant is the first clinically available GHR antagonist. It prevents proper GHR dimerization and therefore inhibits GH action. In this review we have described the discovery and development of pegvisomant. We also reviewed the initial studies in animals and patients with active acromegaly or diabetic complications. In acromegaly, pegvisomant is the most effective treatment for normalizing IGF-I. With respect to long-term safety in acromegalic subjects, more data on tumor size and liver function during long-term treatment are needed.

Preliminary results on the effects of GHR antagonists in animal models of diabetic nephropathy are encouraging. Additionally, the potential use of GHR antagonists for cancer indications is certainly exciting. However, it should be clearly stated that the efficacy of pegvisomant in diabetic patients and patients with cancer remains to be unequivocally established. Characterization of the potential benefit of pegvisomant for these indications is clearly an exciting arena.


    Acknowledgments
 
We thank Dr. W. W. de Herder (Rotterdam, The Netherlands) for his critical review of the manuscript and valuable suggestions.


    Footnotes
 
Abbreviations: ACEi, Angiotensin-converting enzyme inhibitor; GHR, GH receptor; hGH, human GH; NOD, nonobese diabetic; PEG, polyethylene glycol; UAE, urinary albumin excretion.

Received December 27, 2002.

Accepted December 22, 2003.


    References
 Top
 Introduction
 References
 

  1. Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC 1998 Growth hormone and bone. Endocr Rev 19:55–79[Abstract/Free Full Text]
  2. Theill LE, Karin M 1993 Transcriptional control of GH expression and anterior pituitary development. Endocr Rev 14:670–689[Medline]
  3. Lesniak MA, Roth J, Gorden P, Gavin III JR 1973 Human growth hormone radioreceptor assay using cultured human lymphocytes. Nat New Biol 241:20–22[Medline]
  4. de Vos AM, Ultsch M, Kossiakoff AA 1992 Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science 255:306–312[Medline]
  5. Carter-Su C, Rui L, Herrington J 2000 Role of the tyrosine kinase JAK2 in signal transduction by growth hormone. Pediatr Nephrol 14:550–557[CrossRef][Medline]
  6. Baumann G, Shaw MA, Amburn K 1989 Regulation of plasma growth hormone-binding proteins in health and disease. Metabolism 38:683–689[Medline]
  7. Abdel-Meguid SS, Shieh HS, Smith WW, Dayringer HE, Violand BN, Bentle LA 1987 Three-dimensional structure of a genetically engineered variant of porcine growth hormone. Proc Natl Acad Sci USA 84:6434–6437[Abstract]
  8. Waters MJ 1999 The GH receptor. In: Kostoyo JL, Goodman HM, eds. Handbook of physiology. Oxford: Oxford University Press; 397–444
  9. Chen WY, Wight DC, Wagner TE, Kopchick JJ 1990 Expression of a mutated bovine growth hormone gene suppresses growth of transgenic mice. Proc Natl Acad Sci USA 87:5061–5065[Abstract]
  10. Hara K, Sonenberg M 1977 Polyalanylation of bovine somatotropin peptide 96–133. Biochim Biophys Acta 492:95–101[Medline]
  11. Chen WY, White ME, Wagner TE, Kopchick JJ 1991 Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice. Endocrinology 129:1402–1408[Abstract]
  12. Chen WY, Wight DC, Mehta BV, Wagner TE, Kopchick JJ 1991 Glycine 119 of bovine growth hormone is critical for growth-promoting activity. Mol Endocrinol 5:1845–1852[Abstract]
  13. Fuh G, Cunningham BC, Fukunaga R, Nagata S, Goeddel DV, Wells JA 1992 Rational design of potent antagonists to the human growth hormone receptor. Science 256:1677–1680[Medline]
  14. Chen WY, Chen N, Yun J, Wagner TE, Kopchick JJ 1994 In vitro and in vivo studies of the antagonistic effects of human growth hormone analogs. J Biol Chem 269:20806[Free Full Text]
  15. Kopchick JJ, Parkinson C, Stevens EC, Trainer PJ 2002 Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly. Endocr Rev 23:623–646[Abstract/Free Full Text]
  16. Okada S, Chen WY, Wiehl P, Kelder B, Goodman HM, Guller S, Sonenberg M, Kopchick JJ 1992 A growth hormone (GH) analog can antagonize the ability of native GH to promote differentiation of 3T3–F442A preadipocytes and stimulate insulin-like and lipolytic activities in primary rat adipocytes. Endocrinology 130:2284–2290[Abstract]
  17. Pradhananga S, Wilkinson I, Ross RJ 2002 Pegvisomant: structure and function. J Mol Endocrinol 29:11–14[Abstract/Free Full Text]
  18. Veldhuis JD, Bidlingmaier M, Anderson SM, Evans WS, Wu Z, Strasburger CJ 2002 Impact of experimental blockade of peripheral growth hormone (GH) receptors on the kinetics of endogenous and exogenous GH removal in healthy women and men. J Clin Endocrinol Metab 87:5737–5745[Abstract/Free Full Text]
  19. Rodvold KA, van der Lely AJ Pharmacokinetics and pharmacodynamics of B2036-PEG, a novel growth hormone receptor antagonist, in acromegalic subjects. Program of the 81st Annual Meeting of The Endocrine Society, San Diego, CA, 1994, p 145 (Abstract P1-49)
  20. Cunningham BC, Wells JA 1989 High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science 244:1081–1085[Medline]
  21. Thorner MO, Strasburger CJ, Wu Z, Straume M, Bidlingmaier M, Pezzoli SS, Zib K, Scarlett JC, Bennett WF 1999 Growth hormone (GH) receptor blockade with a PEG-modified GH (B2036-PEG) lowers serum insulin-like growth factor-I but does not acutely stimulate serum GH. J Clin Endocrinol Metab 84:2098–2103[Abstract/Free Full Text]
  22. Goffin V, Touraine P 2002 Pegvisomant. Pharmacia. Curr Opin Invest Drugs 3:752–757[Medline]
  23. Govers R, Van Kerkhof P, Schwartz AL, Strous GJ 1997 Linkage of the ubiquitin-conjugating system and the endocytic pathway in ligand-induced internalization of the growth hormone receptor. EMBO J 16:4851–4858[Abstract/Free Full Text]
  24. Govers R, Van Kerkhof P, Schwartz AL, Strous GJ 1998 Di-leucine-mediated internalization of ligand by a truncated growth hormone receptor is independent of the ubiquitin conjugation system. J Biol Chem 273:16426–16433[Abstract/Free Full Text]
  25. Govers R, ten Broeke T, Van Kerkhof P, Schwartz AL, Strous GJ 1999 Identification of a novel ubiquitin conjugation motif, required for ligand-induced internalization of the growth hormone receptor. EMBO J 18:28–36[Abstract/Free Full Text]
  26. Harding PA, Wang X, Okada S, Chen WY, Wan W, Kopchick JJ 1996 Growth hormone (GH) and a GH antagonist promote GH receptor dimerization and internalization. J Biol Chem 271:6708–6712[Abstract/Free Full Text]
  27. Maamra M, Finidori J, Von Laue S, Simon S, Justice S, Webster J, Dower S, Ross R 1999 Studies with a growth hormone antagonist and dual-fluorescent confocal microscopy demonstrate that the full-length human growth hormone receptor, but not the truncated isoform, is very rapidly internalized independent of Jak2-Stat5 signaling. J Biol Chem 274:14791–14798[Abstract/Free Full Text]
  28. Ross RJ, Leung KC, Maamra M, Bennett W, Doyle N, Waters MJ, Ho KK 2001 Binding and functional studies with the growth hormone receptor antagonist, B2036-PEG (pegvisomant), reveal effects of pegylation and evidence that it binds to a receptor dimer. J Clin Endocrinol Metab 86:1716–1723[Abstract/Free Full Text]
  29. Zhang Y, Jiang J, Kopchick JJ, Frank SJ 1999 Disulfide linkage of growth hormone (GH) receptors (GHR) reflects GH-induced GHR dimerization. Association of JAK2 with the GHR is enhanced by receptor dimerization. J Biol Chem 274:33072–33084[Abstract/Free Full Text]
  30. Melmed S 1990 Acromegaly. N Engl J Med 322:966–977.[Medline]
  31. Melmed S 2001 Acromegaly and cancer: not a problem? J Clin Endocrinol Metab 86:2929–2934[Free Full Text]
  32. Orme SM, McNally RJ, Cartwright RA, Belchetz PE 1998 Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab 83:2730–2734[Abstract/Free Full Text]
  33. Fahlbusch R, Honegger J, Buchfelder M 1992 Surgical management of acromegaly. Endocrinol Metab Clin North Am 21:669–692[Medline]
  34. Swearingen B, Barker FG, Katznelson L, Biller BM, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT 1998 Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 83:3419–3426[Abstract/Free Full Text]
  35. Barkan AL, Halasz I, Dornfeld KJ, Jaffe CA, Friberg RD, Chandler WF, Sandler HM 1997 Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab 82:3187–3191[Abstract/Free Full Text]
  36. Barkan AL 2003 Radiotherapy in acromegaly: the argument against. Clin Endocrinol (Oxf) 58:132–135[CrossRef][Medline]
  37. Barrande G, Pittino-Lungo M, Coste J, Ponvert D, Bertagna X, Luton JP, Bertherat J 2000 Hormonal and metabolic effects of radiotherapy in acromegaly: long-term results in 128 patients followed in a single center. J Clin Endocrinol Metab 85:3779–3785[Abstract/Free Full Text]
  38. Biermasz NR, van Dulken H, Roelfsema F 2000 Long-term follow-up results of postoperative radiotherapy in 36 patients with acromegaly. J Clin Endocrinol Metab 85:2476–2482[Abstract/Free Full Text]
  39. Powell JS, Wardlaw SL, Post KD, Freda PU 2000 Outcome of radiotherapy for acromegaly using normalization of insulin-like growth factor I to define cure. J Clin Endocrinol Metab 85:2068–2071[Abstract/Free Full Text]
  40. Thorner MO 2003 Controversy: radiotherapy for acromegaly. Clin Endocrinol (Oxf) 58:136–137[CrossRef][Medline]
  41. van der Lely AJ, de Herder WW, Lamberts SW 1997 The role of radiotherapy in acromegaly. J Clin Endocrinol Metab 82:3185–3186[Free Full Text]
  42. Wass JA 2003 Radiotherapy in acromegaly: a protagonists viewpoint. Clin Endocrinol (Oxf) 58:128–131[CrossRef][Medline]
  43. Abs R, Verhelst J, Maiter D, Van Acker K, Nobels F, Coolens JL, Mahler C, Beckers A 1998 Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab 83:374–378[Abstract/Free Full Text]
  44. Jaffe CA, Barkan AL 1992 Treatment of acromegaly with dopamine agonists. Endocrinol Metab Clin North Am 21:713–735[Medline]
  45. Chanson P, Boerlin V, Ajzenberg C, Bachelot Y, Benito P, Bringer J, Caron P, Charbonnel B, Cortet C, Delemer B, Escobar-Jimenez F, Foubert L, Gaztambide S, Jockenhoevel F, Kuhn JM, Leclere J, Lorcy Y, Perlemuter L, Prestele H, Roger P, Rohmer V, Santen R, Sassolas G, Scherbaum WA, Schopohl J, Torres E, Varela C, Villamil F, Webb SM 2000 Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly. Clin Endocrinol (Oxf) 53:577–586[CrossRef][Medline]
  46. Chanson P, Leselbaum A, Blumberg J, Schaison G 2000 Efficacy and tolerability of the long-acting somatostatin analog lanreotide in acromegaly. A 12-month multicenter study of 58 acromegalic patients. French Multicenter Study Group on Lanreotide in Acromegaly. Pituitary 2:269–276[CrossRef][Medline]
  47. Davies PH, Stewart SE, Lancranjan L, Sheppard MC, Stewart PM 1998 Long-term therapy with long-acting octreotide (Sandostatin-LAR) for the management of acromegaly. Clin Endocrinol (Oxf) 48:311–316[CrossRef][Medline]
  48. Vance ML, Harris AG 1991 Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group. Arch Intern Med 151:1573–1578[Abstract]
  49. Herman-Bonert VS, Zib K, Scarlett JA, Melmed S 2000 Growth hormone receptor antagonist therapy in acromegalic patients resistant to somatostatin analogs. J Clin Endocrinol Metab 85:2958–2961[Abstract/Free Full Text]
  50. van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, Klibanski A, Herman-Bonert V, Melmed S, Vance ML, Freda PU, Stewart PM, Friend KE, Clemmons DR, Johannsson G, Stavrou S, Cook DM, Phillips LS, Strasburger CJ, Hackett S, Zib KA, Davis RJ, Scarlett JA, Thorner MO 2001 Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 358:1754–1759[CrossRef][Medline]
  51. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC, Malsonado M, Rose DR, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF, Davis RJ 2000 Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med 342:1171–1177[Abstract/Free Full Text]
  52. Utiger RD 2000 Treatment of acromegaly. N Engl J Med 342:1210–1211[Free Full Text]
  53. Ho KY 2001 Place of pegvisomant in acromegaly. Lancet 358:1743–1744[CrossRef][Medline]
  54. van der Lely AJ, Muller A, Janssen JA, Davis RJ, Zib KA, Scarlett JA, Lamberts SW 2001 Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient. J Clin Endocrinol Metab 86:478–481[Abstract/Free Full Text]
  55. Melmed S 2003 Treatment of acromegaly. In: Rose BD, ed. UpToDate. Wellesley, MA: UpToDate
  56. Young FG 1937 Permanent diabetes produced by pituitary (anterior lobe) injections. Lancet 2:374.[CrossRef]
  57. Campbell J, Davidson IWF, Lei HP 1950 The production of permanent diabetes by highly purified growth hormone. Endocrinology 46:590
  58. Hansen AP, Johansen K 1970 Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia 6:27–33[Medline]
  59. Yde H 1969 Abnormal growth hormone response to ingestion of glucose in juvenile diabetics. Acta Med Scand 186:499–504[Medline]
  60. Lundbaek K, Christensen NJ, Jensen VA, Johansen K, Olsen TS, Hansen AP, Orskov H, Osterby R 1970 Diabetes, diabetic angiopathy, and growth hormone. Lancet 2:131–133[CrossRef][Medline]
  61. Yde H 1969 The growth hormone dependent sulfation factor in serum from patients with various types of diabetes. Acta Med Scand 186:293–297[Medline]
  62. Flyvbjerg A 1990 Growth factors and diabetic complications. Diabet Med 7:387–399[Medline]
  63. Flyvbjerg A 2000 Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease. Diabetologia 43:1205–1223[CrossRef][Medline]
  64. Janssen JA, Lamberts SW 2000 Circulating IGF-I and its protective role in the pathogenesis of diabetic angiopathy. Clin Endocrinol (Oxf) 52:1–9[CrossRef][Medline]
  65. Flyvbjerg A, Bennett WF, Rasch R, Kopchick JJ, Scarlett JA 1999 Inhibitory effect of a growth hormone receptor antagonist (G120K-PEG) on renal enlargement, glomerular hypertrophy, and urinary albumin excretion in experimental diabetes in mice. Diabetes 48:377–382[Abstract/Free Full Text]
  66. Flyvbjerg A, Orskov H, Alberti G 1993 Growth hormone and insulin-like growth factor I in human and experimental diabetes. Chichester, New York, Brisbane, Toronto, Singapore: Wiley; 1–123
  67. Flyvbjerg A, Landau D, Domene H, Hernandez L, Gronbaek H, LeRoith D 1995 The role of growth hormone, insulin-like growth factors (IGFs), and IGF-binding proteins in experimental diabetic kidney disease. Metabolism 44:67–71[Medline]
  68. Flyvbjerg A, Frystyk J, Thorlacius-Ussing O, Orskov H 1989 Somatostatin analogue administration prevents increase in kidney somatomedin C and initial renal growth in diabetic and uninephrectomized rats. Diabetologia 32:261–265[Medline]
  69. Flyvbjerg A, Marshall SM, Frystyk J, Hansen KW, Harris AG, Orskov H 1992 Octreotide administration in diabetic rats: effects on renal hypertrophy and urinary albumin excretion. Kidney Int 41:805–812[Medline]
  70. Landau D, Segev Y, Afargan M, Silbergeld A, Katchko L, Podshyvalov A, Phillip M 2001 A novel somatostatin analogue prevents early renal complications in the nonobese diabetic mouse. Kidney Int 60:505–512[CrossRef][Medline]
  71. Gronbaek H, Vogel I, Osterby R, Lancranjan I, Flyvbjerg A, Orskov H 1998 Effect of octreotide, captopril or insulin on renal changes and UAE in long-term experimental diabetes. Kidney Int 53:173–180[CrossRef][Medline]
  72. Chen NY, Chen WY, Bellush L, Yang CW, Striker LJ, Striker GE, Kopchick JJ 1995 Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice. Endocrinology 136:660–667[Abstract]
  73. Chen NY, Chen WY, Kopchick JJ 1996 A growth hormone antagonist protects mice against streptozotocin induced glomerulosclerosis even in the presence of elevated levels of glucose and glycated hemoglobin. Endocrinology 137:5163–5165[Abstract]
  74. Bellush LL, Doublier S, Holland AN, Striker LJ, Striker GE, Kopchick JJ 2000 Protection against diabetes-induced nephropathy in growth hormone receptor/binding protein gene-disrupted mice. Endocrinology 141:163–168[Abstract/Free Full Text]
  75. Segev Y, Landau D, Rasch R, Flyvbjerg A, Phillip M 1999 Growth hormone receptor antagonism prevents early renal changes in nonobese diabetic mice. J Am Soc Nephrol 10:2374–2381[Abstract/Free Full Text]
  76. Flyvbjerg A, Rasch R, Effect of growth hormone (GH) receptor antagonist (G120K-PEG) treatment on manifest renal changes in non-obese diabetic (NOD) mice. Proc 32nd Meeting of the American Society of Nephrology, Miami Beach, FL, 1999 (Abstract 3443)
  77. Serri O, Beauregard H, Brazeau P, Abribat T, Lambert J, Harris A, Vachon L 1991 Somatostatin analogue, octreotide, reduces increased glomerular filtration rate and kidney size in insulin-dependent diabetes. JAMA 265:888–892[Abstract]
  78. Jacobs ML, Derkx FH, Stijnen T, Lamberts SW, Weber RF 1997 Effect of long-acting somatostatin analog (Somatulin) on renal hyperfiltration in patients with IDDM. Diabetes Care 20:632–636[Abstract]
  79. Poulsen JE 1953 The Houssay phenomenon in man: recovery from retinopathy in a case of diabetes with Simmond’s disease. Diabetes 2:7–12
  80. Poulsen JE 1966 Diabetes and anterior pituitary insufficiency. Final course and postmortem study of a diabetic patient with Sheehan’s syndrome. Diabetes 15:73–77[Medline]
  81. Boehm BO, Lang GK, Jehle PM, Feldman B, Lang GE 2001 Octreotide reduces vitreous hemorrhage and loss of visual acuity risk in patients with high-risk proliferative diabetic retinopathy. Horm Metab Res 33:300–306[CrossRef][Medline]
  82. Grant MB, Mames RN, Fitzgerald C, Hazariwala KM, Cooper-DeHoff R, Caballero S, Estes KS 2000 The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy: a randomized controlled study. Diabetes Care 23:504–509[Abstract]
  83. Mallet B, Vialettes B, Haroche S, Escoffier P, Gastaut P, Taubert JP, Vague P 1992 Stabilization of severe proliferative diabetic retinopathy by long-term treatment with SMS 201–995. Diabete Metab 18:438–444[Medline]
  84. Van Hagen PM, Baarsma GS, Mooy CM, Ercoskan EM, ter Averst E, Hofland LJ, Lamberts SW, Kuijpers RW 2000 Somatostatin and somatostatin receptors in retinal diseases. Eur J Endocrinol 143(Suppl 1):S43–S51
  85. Smith LE, Kopchick JJ, Chen W, Knapp J, Kinose F, Daley D, Foley E, Smith RG, Schaeffer JM 1997 Essential role of growth hormone in ischemia-induced retinal neovascularization. Science 276:1706–1709[Abstract/Free Full Text]
  86. Growth Hormone Antagonist for Proliferative Diabetic Retinopathy Study Group 2001 The effect of a growth hormone receptor antagonist drug on proliferative diabetic retinopathy. Ophthalmology 108:2266–2272[CrossRef][Medline]
  87. Simo R, Lecube A, Sararols L, Garcia-Arumi J, Segura RM, Casamitjana R, Hernandez C 2002 Deficit of somatostatin-like immunoreactivity in the vitreous fluid of diabetic patients: possible role in the development of proliferative diabetic retinopathy. Diabetes Care 25:2282–2286[Abstract/Free Full Text]
  88. Parkinson C, Drake WM, Roberts ME, Meeran K, Besser GM, Trainer PJ 2002 A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal. J Clin Endocrinol Metab 87:1797–1804[Abstract/Free Full Text]
  89. Pollak M, Blouin MJ, Zhang JC, Kopchick JJ 2001 Reduced mammary gland carcinogenesis in transgenic mice expressing a growth hormone antagonist. Br J Cancer 85:428–430[CrossRef][Medline]
  90. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M 1998 Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279:563–566[Abstract/Free Full Text]
  91. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M 1998 Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351:1393–1396[CrossRef][Medline]
  92. Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ 1999 Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 91:620–625[Abstract/Free Full Text]
  93. Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE 2000 The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 21:215–244[Abstract/Free Full Text]
  94. O’Dell SD, Day IN 1998 Insulin-like growth factor II (IGF-II). Int J Biochem Cell Biol 30:767–771[CrossRef][Medline]
  95. Osborne CK, Clemmons DR, Arteaga CL 1990 Regulation of breast cancer growth by insulin-like growth factors. J Steroid Biochem Mol Biol 37:805–809[CrossRef][Medline]
  96. Friend KE, Radinsky R, McCutcheon IE 1999 Growth hormone receptor expression and function in meningiomas: effect of a specific receptor antagonist. J Neurosurg 91:93–99[Medline]
  97. McCutcheon IE, Flyvbjerg A, Hill H, Li J, Bennett WF, Scarlett JA, Friend KE 2001 Antitumor activity of the growth hormone receptor antagonist pegvisomant against human meningiomas in nude mice. J Neurosurg 94:487–492[Medline]
  98. Huisman TW, Tanghe HL, Koper JW, Reubi JC, Foekens JA, Avezaat CJ, Braakman R, Lamberts SW 1991 Progesterone, oestradiol, somatostatin and epidermal growth factor receptors on human meningiomas and their CT characteristics. Eur J Cancer 27:1453–1457[Medline]
  99. Koper JW, Markstein R, Kohler C, Kwekkeboom DJ, Avezaat CJ, Lamberts SW, Reubi JC 1992 Somatostatin inhibits the activity of adenylate cyclase in cultured human meningioma cells and stimulates their growth. J Clin Endocrinol Metab 74:543–547[Abstract]
  100. Jenkins PJ, Fairclough PD, Richards T, Lowe DG, Monson J, Grossman A, Wass JA, Besser M 1997 Acromegaly, colonic polyps and carcinoma. Clin Endocrinol (Oxf) 47:17–22[Medline]
  101. Alonso M, Galera MJ, Reyes G, Calabuig R, Vinals A, Rius X 1992 Effects of pentagastrin and of the somatostatin analog (SMS 201–995) on growth of CT26 in vivo adenocarcinoma of the colon. Surg Gynecol Obstet 175:441–444[Medline]
  102. Dy DY, Whitehead RH, Morris DL 1992 SMS 201.995 inhibits in vitro and in vivo growth of human colon cancer. Cancer Res 52:917–923[Abstract]
  103. Qin Y, Schally AV, Willems G 1991 Somatostatin analogue RC-160 inhibits the growth of transplanted colon cancer in rats. Int J Cancer 47:765–770[Medline]
  104. Smith JP, Solomon TE 1988 Effects of gastrin, proglumide, and somatostatin on growth of human colon cancer. Gastroenterology 95:1541–1548[Medline]
  105. Qin Y, Schally AV, Willems G 1992 Treatment of liver metastases of human colon cancers in nude mice with somatostatin analogue RC-160. Int J Cancer 52:791–796[Medline]
  106. Duan H, Dagnaes-Hansen F, Rasmussen L, Friend KE, Orskov H, Bennett WF, Flyvbjerg A, GH receptor antagonist treatment inhibits growth of human colorectal carcinoma, COLO205 in nude mice. Proc 5th International Symposium on Insulin-Like Growth Factors Brighton, United Kingdom, 1999 (Abstract P 13)
  107. Friend KE 2000 Targeting the growth hormone axis as a therapeutic strategy in oncology. Growth Horm IGF Res 10(Suppl A):S45–S46
  108. Iftikhar SY, Watson SA, Morris DL 1991 The effect of long acting somatostatin analogue SMS 201.995 therapy on tumour kinetic measurements and serum tumour marker concentrations in primary rectal cancer. Br J Cancer 63:971–974[Medline]
  109. Cascinu S, Del Ferro E, Catalano G 1995 A randomised trial of octreotide vs best supportive care only in advanced gastrointestinal cancer patients refractory to chemotherapy. Br J Cancer 71:97–101[Medline]
  110. Cascinu S, Del Ferro E, Grianti C, Ligi M, Ghiselli R, Foglietti G, Saba V, Lungarotti F, Catalano G 1997 Inhibition of tumor cell kinetics and serum insulin growth factor I levels by octreotide in colorectal cancer patients. Gastroenterology 113:767–772[Medline]
  111. Goldberg RM, Moertel CG, Wieand HS, Krook JE, Schutt AJ, Veeder MH, Mailliard JA, Dalton RJ 1995 A phase III evaluation of a somatostatin analogue (octreotide) in the treatment of patients with asymptomatic advanced colon carcinoma. North Central Cancer Treatment Group and the Mayo Clinic. Cancer 76:961–966[Medline]
  112. Peyrat JP, Bonneterre J, Hecquet B, Vennin P, Louchez MM, Fournier C, Lefebvre J, Demaille A 1993 Plasma insulin-like growth factor-1 (IGF-1) concentrations in human breast cancer. Eur J Cancer 29A:492–497.
  113. Vennin P, Peyrat JP, Bonneterre J, Louchez MM, Harris AG, Demaille A 1989 Effect of the long-acting somatostatin analogue SMS 201–995 (Sandostatin) in advanced breast cancer. Anticancer Res 9:153–155[Medline]
  114. Di Leo A, Ferrari L, Bajetta E, Bartoli C, Vicario G, Moglia D, Miceli R, Callegari M, Bono A 1995 Biological and clinical evaluation of lanreotide (BIM 23014), a somatostatin analogue, in the treatment of advanced breast cancer. A pilot study by the I. T. M. O. Group. Italian Trials in Medical Oncology. Breast Cancer Res Treat 34:237–244[Medline]
  115. Canobbio L, Cannata D, Miglietta L, Boccardo F 1995 Somatuline (BIM 23014) and tamoxifen treatment of postmenopausal breast cancer patients: clinical activity and effect on insulin-like growth factor-I (IGF-I) levels. Anticancer Res 15:2687–2690[Medline]
  116. O’Byrne KJ, Dobbs N, Propper DJ, Braybrooke JP, Koukourakis MI, Mitchell K, Woodhull J, Talbot DC, Schally AV, Harris AL 1999 Phase II study of RC-160 (vapreotide), an octapeptide analogue of somatostatin, in the treatment of metastatic breast cancer. Br J Cancer 79:1413–1418[CrossRef][Medline]
  117. Ingle JN, Suman VJ, Kardinal CG, Krook JE, Mailliard JA, Veeder MH, Loprinzi CL, Dalton RJ, Hartmann LC, Conover CA, Pollak MN 1999 A randomized trial of tamoxifen alone or combined with octreotide in the treatment of women with metastatic breast carcinoma. Cancer 85:1284–1292[CrossRef][Medline]
  118. Friend KE, Flyvbjerg A, Bennett WF, McCutcheon IE, The growth hormone receptor antagonist pegvisomant exhibits antitumor activity in multiple preclinical tumor models. Proc 11th NCI-EORTC-AACR Symposium, Amsterdam, The Netherlands, 2000
  119. Tode B, Serio M, Rotella CM, Galli G, Franceschelli F, Tanini A, Toccafondi R 1989 Insulin-like growth factor-I: autocrine secretion by human thyroid follicular cells in primary culture. J Clin Endocrinol Metab 69:639–647[Abstract]
  120. Hana V, Murphy LJ 1994 Expression of insulin-like growth factors and their binding proteins in the estrogen responsive Ishikawa human endometrial cancer cell line. Endocrinology 135:2511–2516[Abstract]
  121. Dunn SE, Kari FW, French J, Leininger JR, Travlos G, Wilson R, Barrett JC 1997 Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. Cancer Res 57:4667–4672[Abstract]
  122. Dunn SE 2000 Insulin-like growth factor I stimulates angiogenesis and the production of vascular endothelial growth factor. Growth Horm IGF Res 10(Suppl A):S41–S42
  123. Hejna M, Schmidinger M, Raderer M 2002 The clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? Ann Oncol 13:653–668[Abstract/Free Full Text]