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Biomedical subjects

Howard A Reber

Publications and source records attributed to Howard A Reber.

47 records · Page 3Linked to original sources
PubMed2003

An orthotopic nude mouse model for evaluating pathophysiology and therapy of pancreatic cancer.

INTRODUCTION: Orthotopic, clinically relevant animal models are necessary for the study of pathophysiology and therapy for pancreatic cancer. AIMS: To develop a minimally traumatic technique of orthotopic tumor induction, to develop a scoring system to quantify local and systemic tumor spread, and to provide a model with a broad range of well-differentiated to undifferentiated pancreatic cancers. METHODOLOGY: Orthotopic tumors were induced in nude mice by atraumatic pancreatic implantation of two fragments from subcutaneous donor tumors or intrapancreatic injection of human tumor cells (MIAPaCa-2, AsPC-1, HPAF-2, Capan-1). Animals were monitored for 14 weeks or until death. Primary tumor volume, local infiltration, and systemic metastasis were assessed and analyzed at autopsy. Macroscopic findings were confirmed by histologic evaluation. RESULTS: Tumor take rate in the implantation group was 100% for all four cell lines. Marked differences with regard to tumor size, metastatic spread, and survival were found depending on the grade of differentiation. Less differentiated cells (MIAPaCa-2, AsPC-1) caused higher dissemination scores and mortality than better-differentiated cells (HPAF-2, Capan-1). Clinical features included cachexia, jaundice, and malignant ascites. Orthotopic tumor cell injection resulted in an incomplete tumor take rate. Moreover, early artificial abdominal tumor spread was found in injected animals due to microscopic cell loss during the injection procedure. CONCLUSIONS: Orthotopic implantation of donor tumor fragments into nude mice is technically feasible and is superior to the cell injection technique. It results in reproducible local and systemic development of pancreatic cancer that mimics the human disease. A dissemination score may help to better quantify therapeutic effects in future studies.

Animals↗
PubMed2002

Food-derived polyphenols inhibit pancreatic cancer growth through mitochondrial cytochrome C release and apoptosis.

There is increasing evidence that food-derived polyphenols have a beneficial effect for cancers. Our purpose was to determine the effect and mechanism of action of these compounds on pancreatic cancer. We measured effects of quercetin on pancreatic cancer in a nude mouse model. We also investigated the effects of quercetin, rutin, trans-resveratrol and genistein on apoptosis and underlying signaling in pancreatic carcinoma cells in vitro. Quercetin decreased primary tumor growth, increased apoptosis and prevented metastasis in a model of pancreatic cancer. In vitro quercetin and trans-resveratrol, but not rutin, markedly enhanced apoptosis, causing mitochondrial depolarization and cytochrome c release followed by caspase-3 activation. In addition, the effect of a combination of quercetin and trans-resveratrol on mitochondrial cytochrome c release and caspase-3 activity was greater than the expected additive response. The inhibition of mitochondrial permeability transition prevented cytochrome c release, caspase-3 activation and apoptosis caused by polyphenols. Nuclear factor-kappa B activity was inhibited by quercetin and trans-resveratrol, but not genistein, indicating that this transcription factor is not the only mediator of the polyphenols' effects on apoptosis. The results suggest that food-derived polyphenols inhibit pancreatic cancer growth and prevent metastasis by inducing mitochondrial dysfunction, resulting in cytochrome c release, caspase activation and apoptosis.

Animals↗
PubMed2002

Surgical treatment of chronic pancreatitis.

Debilitating abdominal or back pain remains the most common indication for surgery in patients with chronic pancreatitis. The surgical approach to chronic pancreatitis should be individualized based on pancreatic and ductal anatomy, pain characteristics, baseline exocrine and endocrine function, and medical co-morbidity. No single approach is ideal for all patients with chronic pancreatitis. Pancreatic ductal drainage with pancreaticojejunostomy targets patients with a dilated pancreatic duct and produces good early postoperative pain relief; however, 30%-50% of patients experience recurrent symptoms at 5 years. Resection for chronic pancreatitis should be considered (1) when the main pancreatic duct is not dilated, (2) when the pancreatic head is enlarged, (3) when there is suspicion of a malignancy, or (4) when previous pancreaticojejunostomy has failed. Re-sectional strategies include pancreaticoduodenectomy, distal pancreatectomy, total pancreatectomy, duodenum-preserving pancreatic head resection (Beger procedure), or local resection of the pancreatic head with longitudinal pancreaticojejunostomy (Frey procedure). Superior results are obtained when the pancreatic head is resected, either completely (pancreaticoduodenectomy) or partially (Beger or Frey procedure). Although pylorus-preserving pancreaticoduodenectomy remains the gold standard resection procedure, there is evidence that newer operations, such as the Beger resection, may be as effective in regard to pain relief and better in respect to nutritional repletion and preservation of endocrine and exocrine function.

Chronic Disease↗
PubMed2002

VEGF-RII influences the prognosis of pancreatic cancer.

OBJECTIVE: To evaluate whether the vascular endothelial growth factor (VEGF) pathway can be used as a target for effective treatment of pancreatic cancer. SUMMARY BACKGROUND DATA: VEGF and its receptors (VEGF-RI and -RII) are the predominant regulators of tumor neoangiogenesis, a key element for tumor growth and progression. However, VEGF receptor expression has been thought to be limited to endothelial cells, limiting the possibility of targeting it for therapy of pancreatic cancer. METHODS: Protein localization and mRNA were studied in pancreatic cancer specimens, normal pancreas, human pancreatic cancer cell lines, and an endothelial cell line. Cell proliferation was determined by [ H] thymidine uptake. Both VEGF receptors were genetically eliminated by antisense technology. The same approach was used in a murine model of pancreatic cancer in a therapeutic approach. RESULTS: VEGF-RI mRNA and VEGF-RII mRNA were expressed in 17 and 15 of 24 pancreatic cancer samples, respectively. VEGF receptors were found not only in blood vessels but also in pancreatic cancer cells. VEGF-RII expression correlated with poor tumor differentiation and was associated with poorer survival, while VEGF-RI expression did not correlate. VEGF treatment led to extensive growth stimulation in six of seven pancreatic cancer cell lines, which was completely inhibited by antisense treatment against VEGF-RII. Liposome-mediated gene transfer in nude mice with pancreatic tumors markedly reduced local tumor growth and decreased metastatic tumor spread. CONCLUSIONS: The VEGF/VEGF-RII pathway regulates angiogenesis and local tumor growth and spread in pancreatic cancer. Genetic targeting of VEGF-RII blocks local growth and metastatic spread of pancreatic cancer cells in vivo and therefore offers a potential new therapeutic option for patients with this disease.

Adenocarcinoma↗
PubMed2002

Pancreatic surgery.

Over the past year considerable progress has been made in the field of pancreatic surgery. Innovative diagnostic techniques continue to improve the preoperative staging of pancreatic cancer. For patients with cancer and biliary obstruction, preoperative biliary stenting appears to increase the incidence of wound infection after pancreatoduodenectomy but has no effect on other perioperative complications. New information about the molecular biology of pancreatic cancer may begin to influence the surgical approach to the disease. More cases of intraductal papillary mucinous neoplasms are being diagnosed and studied. The impact of adjuvant chemotherapy and chemoradiation on survival has been more clearly defined in a large, randomized trial. In patients with sterile acute necrotizing pancreatitis, conservative nonsurgical management has continued to produce favorable results. For chronic pancreatitis, surgery appears to diminish both chronic pain and recurrent episodes of acute pain.

Journal Article↗
PubMedDate not supplied

Selective inhibition of endothelin receptor A as an anti-angiogenic and anti-proliferative strategy for human pancreatic cancer.

Endothelin-1 (ET-1) plays a major role in tumor proliferation and angiogenesis of various types of cancer acting through endothelin receptors A and B (ET(R)A and ET(R)B). The aim of this study was to analyze the ET-1/ET(R) system in human pancreatic cancer cell lines and to evaluate the effect of a selective endothelin A inhibitor in vitro and in vivo in an orthotopic mouse model. Three different human pancreatic cancer cell lines, MiaPaCa-2, AsPC-1, and Panc-1, were studied. We found that proliferation of human pancreatic carcinoma cells expressing ET(R)A was significantly reduced with a selective antagonist. Hypoxic conditions led to improved results compared to a normoxic environment (MiaPaCa-2: -53% vs. -18%; AsPC-1: -54% vs. -46%). Proliferation of ET(R)A negative Panc-1 cells was not decreased. In vivo, the selective ET(R)A inhibition resulted in reduced angiogenesis as measured by lower microvessel densities (MiaPaCa-2: -47%; AsPC-1: -55%). The blockade of ET(R)A decreased the volume (MiaPaCa-2: -87%; AsPC-1: -28%) and metastatic spread (MiaPaCa-2: -95.5%; AsPC-1: -27%) of receptor-positive tumors, thereby increasing survival in experimental pancreatic cancer. ET(R)A blockade did not show an effect on ET(R)A negative Panc-1 tumors. Therefore, targeting ET(R)A with a selective antagonist might provide a new approach to reducing proliferation and angiogenesis in human pancreatic cancer.

Adenocarcinoma↗
PubMedDate not supplied

Specific targeting of tumor vasculature by diphtheria toxin-vascular endothelial growth factor fusion protein reduces angiogenesis and growth of pancreatic cancer.

Tumor vessels abundantly express receptors for vascular endothelial growth factor (VEGF), a mediator of neoangiogenesis. The aim of this study was to specifically target and damage the vasculature of pancreatic cancer (PaCa) by fusing VEGF to diphtheria toxin (DT), which inhibits protein synthesis of target cells. DT-VEGF fusion protein was produced in vector pGEX-KG and expressed in E. coli SG12036. Human PaCa cell lines (HPAF-2 and AsPC-1) and human endothelial cells (HUVEC) were exposed to DT-VEGF (10 ng/ml - 10,000 ng/ml). Proliferation was assessed after 3 days. One mm(3) fragments of subcutaneous PaCa donor tumors were implanted into the pancreas of nude mice that received either DT-VEGF (200 microg/kg, every other day) or phosphate-buffered saline intraperitoneally for 14 weeks. Tumor volume, metastatic spread, and animal weight were determined at autopsy. Microvessel density was analyzed in CD31-stained tumor sections. Proliferation of PaCa cells was inhibited at high concentrations of DT-VEGF (>1000 ng/ml). DT-VEGF decreased the growth of HUVEC at 10 ng/ml. In vivo, DT-VEGF reduced tumor volume (HPAF-2, 76%; AsPC-1, 53%), microvessel density (HPAF-2, 54%; AsPC-1, 62%), and tumor spread (HPAF-2, 89%; AsPC-1, 50%). Survival was increased (HPAF-2, 7/8 vs. 4/8 animals; AsPC-1, 6/8 vs. 1/8 animals). Weight was not influenced by DT-VEGF. The DT-VEGF effect is due to its toxic action on the tumor vasculature rather than to direct inhibition of PaCa cell growth. DT-VEGF therapy was not associated with systemic side effects.

Angiogenesis Inhibitors↗