Biomedical subjects

William E Fisher

Publications and source records attributed to William E Fisher.

At least 19 recordsLinked to original sources

PubMed2006

Thymosinalpha1 stimulates cell proliferation by activating ERK1/2, JNK, and increasing cytokine secretion in human pancreatic cancer cells.

In this study, we investigated the expression and function of thymosinalpha1 (Thyalpha1) in human pancreatic cancer. We found that human pancreatic cancer cell lines Panc-1, Panc03.27, ASPC-1, and PL45 cells significantly over-expressed the mRNA of Thyalpha1 as compared to the normal human pancreatic ductal epithelium (HPDE) cells.. Thyalpha1 mRNA and protein levels were also over-expressed in clinical pancreatic adenocarcinoma specimens. In addition, synthetic Thyalpha1 significantly promoted Panc-1 cell proliferation and increased phosphorylation of ERK1/2 and JNK. Furthermore, Thyalpha1 increased the secretion of multiple cytokines including IL-10, IL-13, and IL-17 in Panc-1 cells. Thus, Thyalpha1 may have a new role in pancreatic cancer pathogenesis.

Cell Line, Tumor↗

PubMed2006

Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147.

BACKGROUND: Although overexpression of cyclophilin A (CypA) is associated with several types of cancer, its role in pancreatic cancer has not been studied. In this study the expression of CypA and its receptor CD147 on pancreatic cancer was determined as well as the effect of exogenous CypA on pancreatic cancer cell proliferation. METHODS: The expression of CypA and CD147 in human pancreatic cancer cell lines and tissues was determined with real-time reverse transcriptase polymerase chain reaction (RT-PCR), Western blot, and immunostaining. Cell proliferation in response to CypA was performed by [3H]thymidine incorporation assay. Phosphorylation of MAPK and cytokine secretion profiles in pancreatic cancer cells were determined by using the Bio-Plex phosphoprotein assay and cytokine assay. RESULTS: Pancreatic cancer cell lines expressed significantly higher levels of CypA and CD147 than normal human pancreatic ductal epithelium (HPDE) cells. Expression of CypA and CD147 was also substantially higher in human pancreatic adenocarcinoma tissues than those in normal pancreatic tissues. Addition of exogenous CypA significantly stimulated pancreatic cancer cell proliferation in a dose-dependent manner and this effect was effectively blocked by pretreatment with anti-CD147 antibody. In addition, CypA activated ERK1/2 and p38 MAPK signaling pathways and increased the secretion of 2 key cytokines IL-5 and IL-17 in Panc-1 cells. CONCLUSIONS: The expression of CypA and CD147 was significantly increased in both pancreatic cancer cell lines and tissues. Exogenous CypA promotes pancreatic cancer cell growth, which may be mediated through the interaction with CD147 and the activation of ERK1/2 and p38 MAPKs.

Basigin↗

PubMed2006

Effective treatment of pancreatic cancer xenografts with a conditionally replicating virus derived from type 2 herpes simplex virus.

PURPOSE: Pancreatic cancer is a devastating disease that is almost universally fatal because of the lack of effective treatments. We recently constructed a novel oncolytic virus (FusOn-H2) from the type 2 herpes simplex virus. Because the replication potential of FusOn-H2 depends on the activation of the Ras signaling pathway, we evaluated its antitumor effect against pancreatic cancer, which often harbors K-ras gene mutations. EXPERIMENTAL DESIGN: Human pancreatic cancer xenografts were established in nude mice either s.c. or orthotopically (n = 8/group). FusOn-H2 was injected either directly (s.c. tumors) or by the i.v. or i.p. route (orthotopic tumors). Tumor volume, weight, and survival time were recorded for each animal. Statistical analyses were done by Student's t test. RESULTS: A single intratumor injection of FusOn-H2 completely eradicated s.c. pancreatic cancers in all animals. Systemic injection of the oncolytic virus produced clear antitumor effects but did not abolish tumors in any animal. The most striking antitumor effect was seen when the virus was given i.p. Delivery of FusOn-H2 by this route completely eradicated established orthotopic tumors in 75% of the animals and completely prevented local metastases. CONCLUSIONS: FusOn-H2 has potent activity against human pancreatic cancer xenografts and may be a promising candidate for investigative virotherapy of this malignancy.

Animals↗

PubMed2006

Current update of cytokines in pancreatic cancer: pathogenic mechanisms, clinical indication, and therapeutic values.

Pancreatic cancer is the fourth leading cause of cancer death with a 5-year survival less than 5 percent despite rigorous interventions. This largely is due to its late presentation, aggressive metastasis, and a lack of effective adjuvant therapies. Cytokines have been studied in many tumor types, where they have been shown to be an important influence in cancer cell behavior and to have potential as tumor markers, therapeutic targets, or as treatments themselves. Recently, the roles cytokines play in pancreatic cancer have become the subject of intense investigation. However, the story is complicated, largely because of the pleiotropic and overlapping nature of cytokine functions. This article attempts to provide a focused review of recent discoveries in this area by organizing the material along the pathophysiologic tasks a cancer cell must accomplish to achieve malignancy. We examined how cytokines act to create a microenvironment conducive to tumor cell survival and growth, discussed how cytokines affect proliferation, invasion, metastasis, and apoptosis in pancreatic cancer cells, and we summarized how this knowledge has been applied either to target cytokines or use them therapeutically.

Animals↗

PubMed2006

Laparoscopic colon resection early in the learning curve: what is the appropriate setting?

INTRODUCTION: Laparoscopic colon resection (LCR) is a safe and effective treatment of benign and malignant colonic lesions. There is little question that a steep learning curve exists for surgeons to become skilled and proficient at LCR. Because of this steep learning curve, debate exists regarding the appropriate hospital setting for LCR. We hypothesize that outcomes of LCR performed early in the learning curve at a regional medical center (New Hanover Regional Medical Center; NHRMC) and a university medical center (Baylor College of Medicine; BCM) would not be significantly different. METHODS: The first 50 consecutive LCRs performed at each institution between August 2001 and December 2003 were reviewed. Age, mean body mass index (BMI), gender, history of previous abdominal surgery (PAS), operative approach [laparoscopic (LAP) versus hand/laparoscopic assisted (HAL)], conversions (Conv), operative time (OR time), pathology (benign vs. malignant), lymph nodes (LN) harvested in malignant cases, length of stay (LOS), morbidity and mortality were obtained. Continuous data were expressed as mean +/- SD. Data were analyzed by chi, Fisher exact test, or t test. RESULTS: NHRMC patients were on average older females with a higher incidence of PAS. A LAP approach was more frequently performed at BCM (86%), whereas HAL was used more frequently at NHRMC (24%). Conversions to open were similar at both institutions (12%). Benign disease accounted for the majority of operations at both institutions. In cases of malignancy, more LN were harvested at BCM. OR time and LOS were shorter at NHRMC. Complication rates were similar between institutions. There were no anastomotic leaks or deaths. CONCLUSIONS: LCR can be performed safely and with acceptable outcomes early in the learning curve at regional medical centers and university medical centers. Outcomes depend more on surgeons possessing advanced laparoscopic skills and adhering to accepted oncologic surgical principles in cases of malignancy, than on the size or location of the healthcare institution.

Clinical Competence↗

PubMed2005

Value of laparoscopy in the staging of pancreatic cancer.

Pancreatic cancer is a devastating disease that swiftly robs patients of both quality and quantity of life. It is the fourth leading cause of cancer death in the United States. In 2003, there were 31,860 reported new cases with 31,270 deaths occurring due to lack of effective therapy. Eighty percent of patients present with either advanced local or metastatic disease. Dynamic contrast-enhanced computed tomography (CT) has become the current staging test of choice. Laparoscopic staging of pancreatic tumors with the addition of ultrasound can reveal intraparenchymal hepatic metastases, small peritoneal metastases, and critical retroperitoneal tumor-vessel relationships approaching the accuracy of open exploration to determine resectability without significantly increasing morbidity or mortality. However, given the current accuracy of high-quality CT, the routine use of diagnostic laparoscopy in pancreatic cancer is not warranted. Diagnostic laparoscopy is recommended in select patients with primary tumors greater than 4 cm, tumors in the body or tail of the pancreas, patients with equivocal findings of metastasis on CT, ascites, or clinical or laboratory findings suggesting advanced disease such as marked weight loss, hypoalbuminemia, and elevated CA 19-9.

Humans↗

PubMed2005

Abstract writing.

Explore the source record for details and available documents.

Abstracting and Indexing↗

PubMed2005

New roles of a neuropeptide cortistatin in the immune system and cancer.

Cortistatin (CST) is a neuropeptide that strongly resembles somatostatin (SS) structurally and functionally. CST binds to all five SS receptors (SSTR1-SSTR5) with high affinity and exerts its function mainly through SSTRs. Despite many similar functions between these two neuropeptides, they are products of different genes. Recently, some distinct functions and receptor usage of CST have been reported. Some of the interesting functions of CST were not found with SS. Therefore CST could have potential new roles in an ex-neuronal system that regulates immune responses as well as other cellular functions in the body. In this review, we discuss the new functions of CST in the immune system, cancer pathogenesis, and possible CST-specific receptors.

Endothelial Cells↗

PubMed2005

Somatostatin, somatostatin receptors, and pancreatic cancer.

Somatostatin may play an important role in the regulation of cancer growth including pancreatic cancer by interaction with somatostatin receptors (SSTRs) on the cell surface. Five SSTRs were cloned, and the function of these SSTRs is addressed in this review. SSTR-2, SSTR-5, and SSTR-1 are thought to play major roles in inhibiting pancreatic cancer growth both in vitro and in vivo. SSTR-3 may be involved in mediating apoptosis, but the role of SSTR-4 is not clear. In most pancreatic cancers, functional SSTRs are absent. Reintroduction of SSTR genes has been shown to inhibit pancreatic cancer growth in cell cultures and animal models.

Animals↗

PubMed2005

Roles of neuropilins in neuronal development, angiogenesis, and cancers.

Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins that have been characterized as receptors for both semaphorins for neuronal guidance and vascular endothelial growth factor (VEGF) for angiogenesis. Biologic properties of NRPs have been linked to their unique domain structures. However, molecular interaction among NRPs, VEGF, and VEGF receptors is still not clear. Although several types of cancer cells can express NRPs, the role of NRPs in tumor pathogenesis is largely unknown. Thus, future investigations should include determining the effects and mechanisms of NRPs on proliferation, apoptosis, and migration of neuronal , endothelial, and cancer cells. Study of protein-protein interaction, signal transduction pathways, and NRP-mediated gene expression is particularly important to understand NRPs functions, which may have significant clinical applications in the treatment of neurological disorders, cardiovascular diseases, and certain cancers.

Animals↗

PubMed2005

Gene overexpression in pancreatic adenocarcinoma: diagnostic and therapeutic implications.

Pancreatic cancer is the deadliest of cancers, and effective diagnostic and therapeutic strategies are lacking. Global gene expression profiling holds promise for improved diagnosis and treatment. Knowledge of the location and timing of gene overexpression and the function of these genes, including their effects on signaling pathways, is important. These data may be used to develop histologic and serum biomarkers as well as to develop immunotherapeutic, molecular targeting, and gene therapy strategies. We have compiled a list of overexpressed genes in pancreatic cancer for which overexpression was confirmed by reverse transcriptase polymerase chain reaction, immunohistochemistry, and/or in situ hybridization following initial identification by global gene expression profiling. The techniques used in the determination of overexpression, problems encountered in global gene expression profiling, and the diagnostic and therapeutic implications of overexpression are discussed. The S100 gene family, mesothelin, prostate stem cell antigen, and 14-3-3 sigma, may have important clinical implications in pancreatic cancer diagnosis and treatment.

14-3-3 Proteins↗

PubMed2005

Effect of cyclophilin A on gene expression in human pancreatic cancer cells.

BACKGROUND: We previously found that cyclophilin A (CypA) is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147. In this study, we further investigated the effect of CypA on gene expression of several key molecules that are involved in pancreatic cancer cell proliferation. METHODS: Human pancreatic cancer cell lines (Panc-1, MIA PaCa-2, and BxPC-3) and human pancreatic ductal epithelial (HPDE) cells were used. The messenger RNA (mRNA) levels of CypA, CypB, CD147, neuropilins (NRPs), vascular endothelial growth factor (VEGF), and VEGF receptors upon the treatment of exogenous recombinant human CypA were determined by real-time reverse-transcription polymerase chain reaction. RESULTS: Exogenous human recombinant CypA reduced the mRNA levels of NRP-1 and VEGF, but not endogenous CypA, CypB, and CD147, in Panc-1, MIA PaCa-2, and BxPC-3 cells. In contrast, HPDE cells showed a decrease of endogenous CypA and CD147 mRNA, but not detectable changes of CypB, NRPs, and VEGF mRNA levels upon exogenous CypA treatment. CONCLUSIONS: These data show that exogenous CypA downregulates NRP-1 and VEGF expression in pancreatic cancer cells. This effect is different in normal HPDE cells. Thus, soluble CypA may affect cell growth of pancreatic cancer.

Antigens, CD↗

PubMed2005

Transfection of SSTR-1 and SSTR-2 inhibits Panc-1 cell proliferation and renders Panc-1 cells responsive to somatostatin analogue.

BACKGROUND: Somatostatin inhibits cell proliferation through interaction with its cellular receptor, somatostatin receptors (SSTRs). We have previously demonstrated that overexpression of individual SSTR-1 or SSTR-2 genes in receptor-negative pancreatic cancer cells inhibited cell proliferation. We hypothesize that reintroduction of SSTR genes back into pancreatic cancer cells might be an effective gene therapy strategy for pancreatic cancer. STUDY DESIGN: We transfected human pancreatic cancer cell line (Panc-1) with human SSTR-1 and SSTR-2 genes and examined the expression by real-time reverse transcriptase-polymerase chain reaction and immunofluorescence. Panc-1 cell proliferation was determined by [(3)H]-thymidine incorporation assay. Activation of phosphorylated c-Jun N-terminal protein kinase (JNK) and cytokine secretion after SSTR-1 and SSTR-2 transfection were detected by Bio-Plex 4-plex phosphoprotein assay and cytokine assay. RESULTS: Panc-1 cells did not express SSTR-1 or SSTR-2, although Panc-1 cells transfected with SSTR-1 and SSTR-2 genes showed a significant amount of SSTR expression. Cell growth rate in Panc-1 cells transfected with SSTR-1 and SSTR-2 was inhibited about 41%, and the cell proliferation of Panc-1 expressing SSTR-1 and SSTR-2 was further reduced about 12% on treatment with somatostatin analogue as compared with the control group. SSTR-1 and SSTR-2 cotransfected Panc-1 cells activated phosphorylation of JNK and increased secretion of interferon-gamma and interleukin-5. CONCLUSIONS: These findings suggest, for the first time, a synergistic inhibitory effect of multiple SSTRs in response to a somatostatin analogue in Panc-1 cells. These studies may improve our understanding of the mechanism by which SSTR inhibits cell growth and lead to novel gene therapies for pancreatic cancer.

Cell Proliferation↗

PubMed2005

Pancreatic polypeptide administration reduces insulin requirements of artificial pancreas in pancreatectomized dogs.

An artificial endocrine pancreas is a mechanical device that frequently measures blood glucose and adjusts the rate of insulin infusion to maintain normoglycemia. In this study, we evaluated the effect of pancreatic polypeptide (PP) on insulin requirements after total pancreatectomy. However, other endocrine hormones are needed not only to facilitate the effect of insulin, but also to regulate insulin functions in vivo. In this study, the effect of PP infusion on insulin requirements after total pancreatectomy in dogs is examined. After total pancreatectomy, five dogs were supported by artificial endocrine pancreas model STG-22 for 72 h. In a second group of five dogs, both insulin and PP were infused. Mean blood glucose levels and insulin requirements were compared between the two groups. There was no difference in mean plasma glucose levels between the two groups. In all 10 dogs, the mean blood glucose level for 72 h was 110 +/- 4 mg/dL and was tightly controlled between 65 and 190 mg/dL. However, the insulin requirement for the first and second postoperative days in the group treated with PP was significantly less than that of the control group (90.0 +/- 20.8 mU/kg vs. 445.0 +/- 151.9 mU/kg; P < 0.05, and 562.7 +/- 126.5 mU/kg vs. 1007.7 +/- 144.9 mU/kg; P < 0.05, respectively). We conclude that infusion of PP reduces the insulin requirement for the initial 48 h in pancreatectomized dogs treated with an artificial endocrine pancreas.

Animals↗

PubMed2004

Pancreatic carcinoma cells express neuropilins and vascular endothelial growth factor, but not vascular endothelial growth factor receptors.

BACKGROUND: Neuropilins (NRPs) are characterized as coreceptors of vascular endothelial growth factor (VEGF). In the current study, the authors assessed the expression of NRPs, VEGF, and vascular endothelial growth factor receptors (VEGFRs), as well as VEGF-induced cell proliferation, in pancreatic carcinoma cell lines and tissue specimens. METHODS: Human pancreatic carcinoma cell lines (Panc-1 and MIA PaCa-2), normal human pancreatic ductal epithelial cells (HPDE), and human umbilical vein endothelial cells (HUVECs) were cultured. Human pancreatic adenocarcinoma tissue specimens were also studied. Expression levels of NRPs, VEGFRs, and VEGF were determined by real-time polymerase chain reaction analysis and immunostaining. Cell proliferation was examined using a [3H]thymidine incorporation assay. RESULTS: Both NRP-1 and NRP-2 were expressed in Panc-1 cells, HPDE cells, and HUVECs but were expressed minimally in MIA PaCa-2 cells. Panc-1 expressed 30 times more NRP-1 mRNA than NRP-2 mRNA. NRP-1 levels in Panc-1 cells were 5.3 times higher than in HPDE cells but were similar to NRP-1 levels in HUVECs. NRP-2 levels in Panc-1 cells were similar to NRP-2 levels in HPDE cells but lower than NRP-2 levels in HUVECs. Expression of all three VEGFRs was observed only in HUVECs. However, VEGF mRNA was detected in all cell types except for HUVECs. NRP-1 immunoreactivity levels were much higher than NRP-2 immunoreactivity levels in Panc-1 and human pancreatic adenocarcinoma tissue specimens, whereas VEGFRs were not detected in either of these two settings. In response to VEGF165, [3H]thymidine incorporation in Panc-1 cells increased significantly (by 61%; P < 0.01). A monoclonal antibody against human NRP-1 significantly blocked VEGF-induced cell proliferation in Panc-1 cells. CONCLUSIONS: The pancreatic carcinoma cell line Panc-1 and adenocarcinoma tissue specimens expressed high levels of NRP-1 and VEGF, but not VEGFRs, and exogenous VEGF significantly increased NRP-1-mediated, but not VEGFR-mediated, Panc-1 cell proliferation. These data suggested that NRP-1 may be involved in the pathogenesis of pancreatic carcinoma.

Adenocarcinoma↗

PubMed2004

Characterization of somatostatin receptor expression in human pancreatic cancer using real-time RT-PCR.

BACKGROUND: Somatostatin inhibits cell proliferation and may act as a tumor suppressor by interacting with five different somatostatin receptors (SSTRs). We hypothesized that SSTR expression is down-regulated in human pancreatic cancer. In the current study, we used a powerful real-time RT-PCR technique to examine the mRNA expression levels of all five SSTR subtypes in human pancreatic cancer. MATERIALS AND METHODS: Total RNA was extracted from three pancreatic cancer cell lines (Panc-1, MIA PaCa-2, and Hs 766T), three surgical specimens of pancreatic cancer, and adjacent pancreatic tissue, and a pancreatic cancer cell line transfected with the SSTR-2 gene. Specific primers were designed and mRNA levels for the five SSTRs were analyzed with real-time quantitative RT-PCR using a Bio-Rad iCycler system. RESULTS: The pancreatic tumor specimens had a 2.5- and 4.3-fold reduction of SSTR-2 and SSTR-5 mRNA levels, respectively, as compared to their adjacent normal pancreatic tissues. SSTR-1 and SSTR-3 were also detected in both the cancer specimens and the adjacent tissues, but SSTR-4 was absent. Human pancreatic cancer cell lines also expressed SSTR-2 and SSTR-5 mRNA, but not SSTR-1, SSTR-3, and SSTR-4. Up-regulation of SSTR-2 mRNA by 2.2 x 10(4)-fold in Panc-1 cells resulted in receptor expression and growth inhibition. CONCLUSION: Expression of SSTR-2 and SSTR-5 could be important in the growth inhibitory effect of somatostatin in human pancreatic cancer. Down-regulation of SSTR transcription or SSTR mRNA instability may result in loss of a tumor suppressive effect of SSTRs in human pancreatic cancer.

Adenocarcinoma↗

PubMed2004

Specific gene expression and therapy for pancreatic cancer using the cytosine deaminase gene directed by the rat insulin promoter.

Suicide gene therapy has been shown to be an effective means of destroying pancreatic cancer cells, but cell-specific delivery of the gene is required to limit host toxicity. The objective of this study is to determine whether the rat insulin promoter (RIP) will permit cell-specific gene delivery and subsequent cell death in human pancreatic cancer cells. The RIP DNA was amplified using polymerase chain reaction (PCR), and the purified fragment was inserted into pCR-Blunt II-TOPO plasmid at the SpeI site, which contains the coding sequence of yeast cytosine deaminase (CD). Transfection assays were carried out using both RIP-lacZ and RIP-CD DNA constructs in two human pancreatic cancer cell lines, PANC-1 and MIA PaCa-2. Reporter assays using X-gal staining were performed, and the in vitro cytotoxicity was examined in RIP-CD-transfected cells treated with 5-flucytosine for 5 days. The expression levels of CD protein in the transfected cells were determined 2 days after transfection by Western blot analysis. The expression levels of insulin promoter factor (IPF-1/PDX-1) in these human pancreatic cell lines, as well as in freshly isolated human pancreatic cancer specimens, were determined using in situ immunohistochemistry analysis. After transfection with RIP-lacZ, only PANC-1 cells, but not MIA PaCa-2 cells, were positive for RIP-lacZ expression, indicating that RIP-directed reporter gene expression occurred only in PANC-1 cells. After transfection with RIP-CD and treatment with 5-flucytosine, PANC-1 cells had a significantly increased cell death rate compared with that of MIA PaCa-2 cells, suggesting that RIP-directed suicide gene expression occurred only in PANC-1 cells. Western blot analysis demonstrated that only PANC-1 cells were able to express the CD protein and that significantly increased levels of PDX-1 were found in PANC-1 but not in Mia PaCa-2 cells. In situ immunohistochemical analysis of both cell lines showed that PDX-1 was only expressed in the nuclei of PANC-1 cells and not in MIA PaCa-2 cells. Furthermore, two freshly isolated human pancreatic cancer specimens had significantly increased levels of PDX-1. The RIP is activated in PANC-1 cells, but not in Mia PaCa-2 cells, and the mechanism of activation is via PDX-1. Pancreatic cancer-specific cytotoxicity can be achieved with the use of RIP-CD and 5-flucytosine treatment in vitro. Significantly increased levels of PDX-1 have been found in human pancreatic cancer specimens. These results suggest that RIP could be used for cell-specific suicide gene therapy to target human pancreatic tumors.

Antimetabolites↗

PubMed2003

Somatostatin receptor gene transfer inhibits established pancreatic cancer xenografts.

BACKGROUND: Most human pancreatic adenocarcinoma cells do not express somatostatin receptors, and somatostatin does not inhibit the growth of these cancers. We have demonstrated previously that somatostatin inhibits the growth of pancreatic cancers expressing somatostatin receptor subtype-2 (SSTR2), but not receptor-negative cancers. SSTR2 expression may be an important tumor-suppressor pathway that is lost in human pancreatic cancer. We hypothesized that SSTR2 gene transfer would restore the growth-inhibitory response of human pancreatic cancer to somatostatin. MATERIALS AND METHODS: Palpable human pancreatic adenocarcinoma tumors were established on the backs of nude mice by subcutaneous injection of cultured cells (Panc-1). The animals were divided into 5 groups (n = 10/group). Group I served as an untreated control. Group II received an intramuscular injection of the long-acting somatostatin analogue Sandostatin LAR. Group III received Lac-Z expressing adenovirus via intraperitoneal injection. Group IV received SSTR2 expressing adenovirus via intraperitoneal injection. Group V received SSTR2 expressing adenovirus via intraperitoneal injection and an intramuscular injection of Sandostatin LAR. The rate of tumor growth was assessed with calipers. After 28 days, the animals were anesthetized and exsanguanated, and the tumors were excised and weighed. Plasma somatostatin and octreotide levels were measured by radioimmunoassay. Expression of cell-surface somatostatin-receptor protein and known tumor-suppressor proteins was determined by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS: Systemic delivery of SSTR2-expressing adenovirus by intraperitoneal injection resulted in expression of SSTR2 protein in the subcutaneous human pancreatic cancers. Final tumor weight was significantly decreased in the groups expressing SSTR2 receptors compared to the other 3 groups. Treatment with Sandostatin LAR increased plasma octreotide levels as determined by radioimmunoassay, but had no significant effect on tumor growth. Western blot analysis revealed an up-regulation of the cyclin-dependent kinase inhibitors p27 and p16 in the SSTR2 transfected tumors. CONCLUSIONS: Expression of SSTR2 by human pancreatic cancer causes significant slowing of tumor growth by a mechanism independent of exogenous somatostatin. The mechanism may involve up-regulation of known tumor-suppressor proteins. Restoration of SSTR2 gene expression deserves further study as a potential gene-therapy strategy in human pancreatic cancer.

Adenocarcinoma↗