Pegvisomant: structure and function

Pradhananga, Sarbendra; Wilkinson, Ian; Ross, R. J. M.

doi:10.1677/jme.0.0290011

Cited by 68 publications

(50 citation statements)

References 10 publications

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“…Acromegaly patients with high levels of circulating GH exhibit increased incidence of colon adenomas (45). Pegvisomant, a GHR antagonist, prevents GH binding by disrupting internal rotation and activation of downstream GH signaling (46)(47)(48). To examine whether clinical inhibition of GH signaling alters colon tissue p53 expression, seven acromegaly subjects were prospectively enrolled to undergo colon mucosal biopsy before and after 8 wk of pegvisomant treatment (Table S1).…”

Section: Resultsmentioning

confidence: 99%

Growth hormone is permissive for neoplastic colon growth

Chesnokova

Zonis

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Fig. 6. GH induces EMT, suppresses apoptosis, and increases motility. Western blot analysis of PTEN and EMT factors in (A) hNCC and (B) HCT116 cells treated with indicated doses of GH for 24 h. (C) Western blot analysis of cleaved caspase 3 in cells treated with GH (500 ng/mL) for 24 h. Experiments were performed at least three times, and representative results shown. (D) Migration of hNCC and HCT116 cells treated with GH (500 ng/mL) and harvested 48 h after plating. (E) Migration of HCT116 cocultured for 48 h with hCF infected with lentivector or lentiGH. In D and E, for quantification, the number of migrated cells per 1,000 cells in five randomly chosen fields in each duplicate transwell were counted and means calculated. Results are presented as mean ± SEM of three independent experiments; *P < 0.05. (F) Number of colonies and arbitrary colony size formed in soft agar by HCT116 cells cocultured with hCF infected with lentivector or lentiGH, and tested for anchorage independent growth. Colony size was determined using ImageJ software. Results are presented as mean ± SEM of duplicates from two independent experiments; **P < 0.01 vs. control. In D-F, the differences between groups were analyzed using two-tailed unpaired Student t test.

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Section: Resultsmentioning

confidence: 99%

Growth hormone is permissive for neoplastic colon growth

Chesnokova

Zonis

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…© 2007 American Association for Cancer clincancerres.aacrjournals.org Downloaded from pegvisomant was well tolerated at biweekly doses up to 40 mg/ kg (data not shown). 1 Thus, the weekly i.v. administration may be a viable regimen to be evaluated in further clinical trials of pegvisomant in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Clinical Pharmacodynamic Effects of the Growth Hormone Receptor Antagonist Pegvisomant: Implications for Cancer Therapy

Yin

Vreeland

Schaaf

et al. 2007

Clinical Cancer Research

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Purpose: The present study evaluated and compared the efficacy of pegvisomant and octreotide in blocking the growth hormone (GH) axis in humans based on pharmacodynamic biomarkers associated with the GH axis. The study also evaluated the safety of pegvisomant given at high s.c. doses for 14 days. Experimental Design: Eighty healthy subjects were enrolled in five cohorts: cohorts 1 to 3, s.c. pegvisomant at 40, 60, or 80 mg once daily × 14 days (n = 18 per cohort); cohort 4, s.c. octreotide at 200 μg thrice daily × 14 days (n = 18); and cohort 5, untreated control (n = 8). Serial blood samples were collected to measure plasma concentrations of total insulin-like growth factor type I (IGF-I), free IGF-I, IGF-II, IGF-binding protein 3 (IGFBP-3), and GH in all subjects and serum pegvisomant concentrations in subjects of cohorts 1 to 3. All subjects receiving treatment were monitored for adverse events (AE). Results: After s.c. dosing of pegvisomant once daily for 14 days, the mean maximum suppression values of total IGF-I were 57%, 60%, and 62%, at 40, 60, and 80 mg dose levels, respectively. The maximum suppression was achieved ∼7 days after the last dose and was sustained for ∼21 days. Pegvisomant also led to a sustained reduction in free IGF-I, IGFBP-3, and IGF-II concentrations by up to 33%, 46%, and 35%, respectively, and an increase in GH levels. In comparison, octreotide resulted in a considerably weaker inhibition of total IGF-I and IGFBP-3 for a much shorter duration, and no inhibition of IGF-II. AEs in pegvisomant-treated subjects were generally either grade 1 or 2. The most frequent treatment-related AEs included injection site reactions, headache, and fatigue. Conclusions: Pegvisomant at well-tolerated s.c. doses was considerably more efficacious than octreotide in suppressing the GH axis, resulting in substantial and sustained inhibition of circulating IGF-I, IGF-II, and IGFBP-3 concentrations. These results provide evidence in favor of further testing the hypothesis that pegvisomant, through blocking the GH receptor–mediated signal transduction pathways, could be effective in treating tumors that may be GH, IGF-I, and/or IGF-II dependent, such as breast and colorectal cancer.

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“…33,35,36 Covalent attachment of the hGH with PEG has been shown to increase its circulating half-life. [37][38][39][40][41] However, there are no literature reports on the solid-state stability of the lyophilized PEGylated human growth hormone.…”

Section: Impact Of Processing and Storage On The Stability Of Freeze-mentioning

confidence: 99%