Andrew Abi-Chaker

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Gastrin releasing-peptide (GRP) is a potent growth factor in many malignancies. Benign prostatic hyperplasia (BPH) is a progressive age-related proliferation of glandular and stromal tissues; various growth factors and inflammatory processes are involved in its pathogenesis. We have demonstrated that potent antagonists of GRP inhibit growth of experimental human tumors including prostate cancer, but their effect on models of BPH has not been studied. Here, we evaluated the effects of GRP antagonist RC-3940-II on viability and cell volume of BPH-1 human prostate epithelial cells and WPMY-1 prostate stromal cells in vitro, and in testosterone-induced BPH in Wistar rats in vivo. RC-3940-II inhibited the proliferation of BPH-1 and WPMY-1 cells in a dose-dependent manner and reduced prostatic cell volume in vitro. Shrinkage of prostates was observed after 6 wk of treatment with RC-3940-II: a 15.9% decline with 25 μg/d; and a 18.4% reduction with 50 μg/d (P < 0.05 for all). Significant reduction in levels of proliferating cell nuclear antigen, NF-κβ/p50, cyclooxygenase-2, and androgen receptor was also seen. Analysis of transcript levels of genes related to growth, inflammatory processes, and signal transduction showed significant changes in the expression of more than 90 genes (P < 0.05). In conclusion, GRP antagonists reduce volume of human prostatic cells and lower prostate weight in experimental BPH through direct inhibitory effects on prostatic GRP receptors. GRP antagonists should be considered for further development as therapy for BPH.

Mechanisms of synergism between antagonists of growth hormone-releasing hormone and antagonists of luteinizing hormone-releasing hormone in shrinking experimental benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) affects aging men. Combined therapy with antagonists of growth hormone‐releasing hormone (GHRH) and of luteinizing hormone‐releasing hormone (LHRH or GnRH) induces prostate shrinkage in rat models. We investigated the mechanisms of action of this combination on cell cycle traverse and expression of prostatic genes.

Effect of novel growth hormone-releasing hormone antagonists on growth of experimental renal cell carcinomas.

469 Background: Although targeted therapy has improved the clinical outcome for patients with metastatic renal cell carcinoma (RCC), a complete response is rare and therapy has adverse effects. Early antagonists of growth hormone-releasing hormone (GHRH) were shown to inhibit experimental RCC cell line, Caki-1, in vitro and in vivo. Herein, we investigate the effects of novel and highly potent antagonists of GHRH of MIA class on the growth of three RCC cell lines. METHODS The expression of GHRH receptor in all three cell lines was evaluated by ligand competition studies. The influence of GHRH antagonists MIA-602, MIA-604, MIA-606, and MIA-690 on cell viability was assessed by MTS assay in ACHN, A498, and 786-0 human RCC cells. GHRH antagonists were given at dose of 5µg daily in these three nude-mice xenograft models. Cell cycle parameters were analyzed by laser flow cytometry. RESULTS Ligand competition studies revealed specific, high affinity binding sites for GHRH receptor in all three RCC cell lines. GHRH antagonists inhibited the proliferation of all three RCC cells in a dose dependent manner. GHRH antagonists caused significant inhibition of tumor growth of ACHN, A498, and 786-0 RCCs ranged from 53-75% after 35 days of treatment (p<0.001). Treatment of ACHN cells with MIA-690 (10µM) led to a significant increase in number of cells with subG1DNA content, suggesting apoptosis. CONCLUSIONS The effectiveness of the novel GHRH antagonists in inhibiting growth of experimental RCC models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists is mainly due to direct inhibitory effects exerted through GHRH receptors. Biochemical and histological evaluation is needed to explore the mechanisms of action of GHRH antagonists in RCC.

Abstract 91: Powerful inhibition of human renal cell carcinomas with antagonists of growth hormone-releasing hormone (GHRH): a preclinical study.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC BACKGROUND: Advances in targeted medical thereapy has demonstrated improved clinical outcomes for patients with metastatic renal cell carcinoma (RCC), however, a complete response is rare and current therapy has various adverse effects that are unfortunately not as rare. Early antagonists of growth hormone-releasing hormone (GHRH) were shown to inhibit experimental RCC cell line, Caki-1, in vitro and in vivo. GHRH itself acts as an autocrine/paracrine growth factor in human cancers, including RCC. Herein, we investigate the effects of novel and highly potent new antagonists of GHRH on the growth of three RCC cell lines with different primary tumor sites. METHODS: The expression of GHRH receptor in all three cell lines was evaluated by ligand competition studies. The in vitro influence of GHRH antagonists designated MIA-602, MIA-604, MIA-606 and MIA-690 on cell viability was assessed by MTS assay in ACHN, A498, and 786-0 human RCC cells. GHRH antagonists were given at a dose of 5μg daily in these three nude-mice xenograft models in vivo. Cell cycle parameters were analyzed by laser flow cytometry. RESULTS: Ligand competition studies revealed specific, high affinity binding sites for GHRH receptor in all three RCC cell lines. GHRH antagonists inhibited the proliferation of all three RCC cells in a dose dependent manner. GHRH antagonists caused significant inhibition of tumor growth of ACHN, A498, and 786-0 RCCs ranging from 53-75% after 35 days of treatment (p<0.001). Treatment of ACHN and A498 cells with 10μM MIA-602 and MIA-690 (5 and 10μM) led to a significant increase in number of cells with subG1 DNA content, suggesting apoptosis. CONCLUSIONS: The effectiveness of the new and novel GHRH antagonists in inhibiting growth of experimental RCC models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists is mainly due to direct suppressive effects exerted through GHRH receptors. Further biochemical and histological evaluation is warranted to explore the mechanisms of action of GHRH antagonists in RCC. Citation Format: Ferenc G. Rick, Andrew Abi-Chaker, Luca Szalontay, Norman L. Block, Gabor Halmos, Mehrdad Nadji, Andrew V. Schally. Powerful inhibition of human renal cell carcinomas with antagonists of growth hormone-releasing hormone (GHRH): a preclinical study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 91. doi:10.1158/1538-7445.AM2013-91

Strategies to Treat Venous Reflux Disease

An estimated 30% of adults in the United States have some degree of venous reflux disease. These may range from subclinical reflux to aesthetic asymptomatic varicosities noted in the superficial tissue to advanced chronic venous disease (CVD) with ulcerations and pain. Given the variety of presentations of patients with venous reflux disease, CVD can be classified using the revised CEAP classification system and/or by using the revised Venous Clinical Severity Score (VCSS). Various treatment modalities are available, including nonoperative and operative management. This chapter focuses on the various modalities available for use and the risks and benefits of each modality and discusses some controversial topics in venous reflux disease. At a minimum, clinical follow-up should include CEAP classification and VCSS scores.

Successful Revascularization of Aortic Arch in a 39-Year-Old Blunt Trauma Patient with Acute Diffuse Axonal Injury without the Use of Systemic Anticoagulation

Blunt traumatic aortic injury is the second leading cause of death in trauma patients aged 4-34 years. Of the patients who are able to receive treatment, mortality rates as high as 40% have been reported. Endovascular repair options have allowed for more expeditious repairs with reduced iatrogenic trauma; however, when the injury involves the ascending aorta or arch, current endografts lack fenestrations needed for cerebral blood flow. Traditionally, on pump, cardiopulmonary bypass with systemic anticoagulation has been used to repair these injuries. In this paper, we describe a unique case of repairing a large traumatic aortic arch pseudoaneurysm in the setting of which systemic anticoagulation is contraindicated. The patient is a 39-year-old otherwise healthy Hispanic male who presented to Ryder Trauma Center in Miami, Florida, following a motor vehicle collision and found to have multiple intracranial hemorrhages and a large aortic pseudoaneurysm of the distal ascending aorta. In lieu of standard cardiopulmonary bypass, a hybrid approach was utilized. Cranial blood flow was maintained using a temporary extra-anatomical left femoral to bilateral carotid bypass during endovascular coverage of the aortic arch. Aortic arch revascularization was then achieved by means of in situ laser fenestration of the innominate artery followed by a right-to-left carotid-carotid-subclavian bypass. This case demonstrates the viability of a hybrid vascular repair of a complex aortic disruption without the use of systemic anticoagulation in the setting of contraindicated or unknown risk of systemic anticoagulation. Further research is warranted on whether emergent traumatic cases with contraindications to anticoagulation can be performed in a similar fashion to safely reduce the morbidity and mortality associated with aortic disruptions.