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D S Longnecker

Publications and source records attributed to D S Longnecker.

At least 55 records · Page 3Linked to original sources
PubMed1992

Overexpression of cholecystokinin receptors in azaserine-induced neoplasms of the rat pancreas.

Cholecystokinin (CCK) is a growth factor for normal pancreas. Numerous studies also suggest that CCK promotes pancreatic carcinogenesis in the rat. Our previous studies suggested that growth of preneoplastic pancreatic foci was stimulated by CCK more than that of normal pancreas. We hypothesized that such differential growth might be due to increased numbers of CCK receptors in neoplastic tissue. Azaserine-induced pancreatic carcinoma (DSL6) had an increased high-affinity CCK receptor binding capacity of 122 +/- 23 (SD) fmol/mg protein compared to 12 +/- 2 fmol/mg protein in normal pancreas (P less than 0.001). The Kd of the high-affinity site was 0.33 +/- 0.04 nM for carcinoma and 0.46 +/- 0.08 nM for normal pancreas (P less than 0.01). The amount of cholecystokinin octapeptide (CCK-8) bound to high-affinity receptor was 8.6 +/- 1.9 fmol/mg protein for DSL6 compared to 0.6 +/- 0.2 fmol/mg protein in normal pancreas (P less than 0.001). Azaserine-induced premalignant nodules were compared to remaining internodular pancreas. Nodules demonstrated a mean high-affinity CCK receptor binding capacity of 38 +/- 9 fmol/mg protein compared to 6 +/- 3 fmol/mg protein in internodular pancreas (P less than 0.001). The amount of CCK-8 bound to high-affinity receptor was 3.1 +/- 0.8 fmol/mg protein in nodules compared to 0.6 +/- 0.3 fmol/mg protein in internodular pancreas (P less than 0.001). Overexpression of high-affinity CCK-8 receptor in premalignant and malignant azaserine-induced tumors may result in a growth advantage relative to normal pancreas.

Animals↗
PubMed1992

The pancreatic duct cell.

A conference entitled "The Pancreatic Duct Cell: Physiology and Pathophysiology" was held September 26-29, 1991, at the Engineering Society Club of Baltimore. The conference was organized by a committee consisting of John Williams of the University of Michigan (Co-Chair), Daniel Longnecker of Dartmouth Medical School (Co-Chair), Barry Agent of Newcastle Upon Tyne, Raymond Frizzell of the University of Alabama at Birmingham, Sherwood Githens of the University of New Orleans, and Sarah Kalser of the NIDDK. The meeting was sponsored by the NIDDK with contributions from NCI, NIDR, ADAMHA, and the American Gastroenterological Association. About 100 investigators from the United States, England, Canada, Germany, Norway, and Israel attended the conference. The participants were based in a number of distinct disciplines including both basic and clinical sciences. While the main focus was on pancreatic ducts, comparison of salivary and bile ducts was also included.

Animals↗
PubMed1992

Characterization of the ELSV transgenic mouse model of pancreatic carcinoma. Histologic type of large and small tumors.

Carcinomas of the pancreas that developed in Tg(Ela-1, SV40E)Bri18 and Tg(Ela-1, SV40E+Ela-1, neo)Bri19 strains of transgenic mice were classified into eight histologic patterns. Most were variants of acinar cell carcinoma, but cystic and undifferentiated carcinomas were found. The spectrum of phenotypes was similar in small and large carcinomas, but the small group included a higher fraction of well-differentiated tumors and fewer poorly differentiated and anaplastic tumors. The incidence of islet cell tumors was far higher in the Bri18 strain (77%) than in the Bri19 strain (1.6%). Islet cell hyperplasia was much more prevalent in Bri18 than Bri19 mice. In both strains, the nontumorous pancreas showed acinar cell dysplasia with a more abnormal and distinctive pattern in the Bri19 strain. While the spectrum of exocrine tumor phenotypes is similar, significant differences occurred between these two transgenic mouse strains as models for pancreatic carcinogenesis.

Adenoma, Islet Cell↗
PubMed1991

Hormones and pancreatic cancer.

Several polypeptide hormones have been demonstrated to stimulate or inhibit cell division in the cells of the pancreas. Therefore, receptors for these hormones have been sought in pancreatic carcinomas, and several examples have been reported. In some instances, stimulation of tumor growth by the corresponding peptide has been demonstrated or growth was blocked by a receptor antagonist. Receptors and binding proteins for steroid hormones also have been reported in carcinomas of the pancreas. In experimental carcinogenesis, the growth of preneoplastic lesions and incidence of neoplasms have been influenced by both peptide and steroid hormones in some species. Experimental manipulation of sex steroid hormones has yielded both inhibition and enhancement of growth of human and rat pancreatic cancers, but thus far, clinical trials have failed to document advantageous approaches for steroid or antihormonal therapy. These observations imply that trophic or growth-inhibiting polypeptide and steroid hormones may serve as promoters or inhibitors of carcinogenesis in the pancreas, and may influence the growth of established carcinomas. Receptor blockers may provide a clinical approach for slowing the growth of some cancers.

Animals↗
PubMed1991

Inhibition of the growth of transplanted rat pancreatic acinar carcinoma with octreotide.

The effects of octreotide on transplanted azaserine-induced pancreatic acinar tumours were investigated in the rat. When tumours became palpable, rats were treated either with octreotide (40 micrograms/kg per day, by infusion) or NaCl 0.9% (controls) for 14 days. Tumours were then analysed for their size, composition and somatostatin receptors. Octreotide induced a 80% reduction in tumour growth rate during the first 2 days of treatment. This rate was less marked from day 4 to day 15. The tumour weight, protein, DNA, RNA and enzyme content were reduced in parallel by 50 to 60%. A homogeneous distribution density and a high affinity of somatostatin receptors were found by receptor autoradiography and in vitro binding assays in tumours of both groups. These findings indicate that octreotide reduces the growth rate of the transplanted pancreatic acinar tumour and may exert its inhibitory effect directly via specific somatostatin receptors on tumour cells.

Animals↗
PubMed1991

Inhibitory effect of streptozotocin on tumor development in transgenic mice bearing an elastase I-SV40 T-antigen fusion gene.

Transgenic mice, bearing a fusion gene of rat elastase I promoter and SV40 T-antigen, developed acinar cell tumors of the pancreas, as predicted by the model. In addition, they developed insulinomas and somatostatin (delta)-cell hyperplasia of the pancreatic islets. The insulinomas and the delta-cell hyperplasia appeared to be functional, as evidenced by changes in plasma glucose, insulin, and somatostatin. Streptozotocin, which has been shown to inhibit pancreatic carcinogenesis in the hamster model, significantly reduced the numbers of insulinomas and delta-cell hyperplasias. Streptozotocin did not cause a statistically significant reduction in exocrine tumors.

Animals↗
PubMed1991

Preneoplastic and neoplastic lesions in the pancreas of rats fed choline-devoid or choline-supplemented diets.

Groups of male Fischer 344 rats were chronically fed semipurified choline-devoid or choline-supplemented diets, high in fat (15%), and containing or not containing 0.06% phenobarbital. Atypical acinar cell nodules were observed in the pancreas of the rats, irrespective of the diet fed, with incidences varying from 38% to 100% in the various groups. No consistent differential effects of the dietary treatments on the incidence and growth of the nodules were evident, even though the diameter of the nodules tended to be greater in some of the groups fed the basal choline-devoid diet. The vast majority of the nodules were of the acidophilic type. More advanced pancreatic acinar cell lesions were observed in a few of the rats. Since the rats were not exposed to a chemical carcinogen(s), development of the nodules and of the more advanced lesions, even in rats fed the control diets, was most likely due to evolution of endogenous (spontaneous) initiated pancreatic cells, promoted primarily by the feeding of semipurified diets with a high fat content.

Animals↗
PubMed1991

Marked differences in immunocytological localization of [3H]estradiol-binding protein in rat pancreatic acinar tumor cells compared to normal acinar cells.

[3H]Estradiol can bind to a specific protein in normal rat pancreatic acinar cells. Electron microscopic immunocytochemical analysis has shown this protein to be localized primarily in the rough endoplasmic reticulum and mitochondria. Rat exocrine pancreatic tumor cell lines, whether grown in tissue culture (AR42J) or as a tumor mass after sc injection into rats (DSL-2), lacked detectable amounts of this [3H]estradiol-binding protein (EBP), as determined by the dextran-coated charcoal assay. Furthermore, primary exocrine pancreatic neoplasms induced with the carcinogen azaserine contained little or no detectable [3H]estradiol-binding activity. However, electron immunocytochemical studies of transformed cells indicated the presence of material that cross-reacted with antibodies prepared against the [3H]EBP. The immunopositive reaction in transformed cells was localized almost exclusively in lipid granules. Such lipid organelles in normal acinar cells, although present less frequently than in transformed cells, have never been observed to contain EBP-like immunopositive material. Presumably, the aberrant localization of EBP in these acinar tumor cells results in loss of function of this protein, which in normal pancreatic acinar cells appears to exert a modulating influence on zymogen granule formation and the process of secretion.

Animals↗
PubMed1991

Characterization of preneoplastic and neoplastic lesions in the rat pancreas.

Nodules of acinar cells with increased proliferative potential develop in the pancreas of carcinogen-treated rats and in untreated aged rats. Large nodules are classed as adenomas. Phenotypic and genotypic characteristics of nodule cells were compared with normal pancreas and transplantable acinar cell carcinomas by several methods. Nuclei of acinar cells from normal pancreas, adenomas, and three carcinomas in situ had normal diploid DNA content as determined by flow cytometry. One of two primary carcinomas had a hypodiploid DNA content. Two of three transplantable carcinomas were aneuploid with a DNA content in the tetraploid range. Explants from nodules and adenomas failed to grow in soft agar, whereas several carcinomas were positive in this assay. A primary carcinoma was serially transplanted, but transplantation of nodules or adenomas failed. Transfection of DNA from carcinomas in situ yielded a higher frequency of NIH 3T3 transformants than DNA from adenomas. DNAs from the transformants did not contain ras sequences. These studies indicate that cells from nodules and adenomas have low growth potential and lack critical phenotypic and genotypic characteristics of transformed malignant cells that were present in some primary and transplanted carcinomas.

Adenoma↗
PubMed1990

Characterization of the elastase 1-simian virus 40 T-antigen mouse model of pancreatic carcinoma: effects of sex and diet.

Elastase 1-simian virus transgenic mice, strain Tg(Ela-1, SV40E) Bri18, were studied to characterize the development of pancreatic neoplasms. The incidence of pancreatic carcinomas was compared in groups of male and female mice fed one of three diets chosen because of their effect on the development of pancreatic carcinomas in other animal models. Male mice developed more exocrine carcinomas than female mice and their tumors were larger. Groups fed chow had fewer exocrine carcinomas than groups fed purified diets. The level of fat in the latter diets, 5 versus 20% corn oil, did not alter tumor incidence. An unexpectedly high incidence of islet cell tumors was found in all dietary groups, with a higher incidence in females than in males.

Adenoma, Islet Cell↗
PubMed1990

Activation of c-Ki-ras not detectable in adenomas or adenocarcinomas arising in rat pancreas.

The objective of this study was to determine whether activation of c-Ki-ras occurs in carcinogen-induced rat pancreatic tumors. DNAs from 27 samples, which included adenomas, carcinomas in situ, and adenocarcinomas arising in azaserine-treated rats and corn oil-gavaged rats along with a nafenopin-induced rat pancreatic adenocarcinoma were examined for mutation of c-Ki-ras at codons 12, 13, and 61 by using the polymerase chain reaction. Our results indicate that activation of c-Ki-ras is not a common event during pancreatic carcinogenesis in the rat.

Adenocarcinoma↗
PubMed1990

Expression of c-myc, c-raf-1, and c-Ki-ras in azaserine-induced pancreatic carcinomas and growing pancreas in rats.

We examined the pattern of expression of several proto-oncogenes during nonneoplastic growth and in acinar cell neoplasms in the rat pancreas. The levels of c-myc, c-raf-1, and c-Ki-ras mRNAs were increased in regenerating pancreata following surgical partial pancreatectomy and following administration of camostat. We also investigated proto-oncogene expression associated with the progression of pancreatic cancers in azaserine-treated rats. Injection of a single dose (30 mg/kg) of azaserine (O-diazoacetyl-L-serine) to 14-d-old rats leads to a variety of neoplastic lesions in the rat pancreas. Total RNA was isolated from lesions in various stages of tumor progression, including adenomas, carcinomas in situ, and invasive carcinomas. We observed increased expression of c-myc, c-raf-1, and c-Ki-ras in azaserine-induced adenomas and carcinomas. Actin expression was also increased in these tissues, whereas amylase expression was variable. However, when compared to the normal growing pancreas, the level of proto-oncogene expression in the adenomas and carcinomas was disproportionate to the degree of cellular division in those tissues. Thus, the alterations induced by azaserine apparently caused a deregulated increase in expression of cellular oncogenes associated with growth regulation.

Adenoma↗
PubMed1990

Evaluation of promotion of pancreatic carcinogenesis in rats by benzyl acetate.

Benzyl acetate was found to induce liver tumours and gastric squamous neoplasms in mice in a chronic bioassay conducted through the National Toxicology Program. An increased incidence of acinar cell adenomas of the pancreas of F344 rats was noted in the bioassay, but the significance of these lesions was confounded because the benzyl acetate was given by gavage in corn oil. The use of corn oil as a vehicle has been shown to enhance the growth of such lesions in the rat pancreas. The current studies were undertaken to evaluate benzyl acetate alone as an initiator and promoter of carcinogenesis in the pancreas. Alkaline elution analysis of acinar cell DNA showed no evidence of damage 1 hr after administration of benzyl acetate. Significant stimulation of growth of azaserine-induced foci was observed in a 6-month study, and a low but significant incidence of carcinoma in situ was observed in rats fed benzyl acetate in the diet for 2 yr. These experiments suggest that benzyl acetate is a weak promoter of the growth of carcinogen-induced and spontaneous pre-neoplastic foci in the pancreas.

Adenoma↗
PubMed1990

Hyperplasia and tumors of the islets of Langerhans in mice bearing an elastase I-SV40 T-antigen fusion gene.

Transgenic mice bearing a fusion gene consisting of rat elastase I 5' flanking DNA fused to the early-coding (T-antigen) region of the SV40 genome (ELSV mice) develop carcinomas of the acinar cells of the exocrine pancreas. Histopathological examination of pancreatic tissue from 79 such animals revealed that, in addition to acinar cell neoplasms, ELSV mice develop two distinct lesions of the islets of Langerhans. By the age of 26 weeks, 36% of the mice had developed insulinomas. Starting at 8 weeks of age, the mice also developed D (somatostatin)-cell hyperplasia, which began at the periphery of the islets but which in advanced cases resulted in nearly complete replacement of other islet cell types by D-cells. By 26 weeks of age, 85% of the mice examined demonstrated the D-cell abnormality. Both the insulinomas and D-cell lesions were negative by immunohistochemistry for T-antigen, which was, however, demonstrated in acinar cell neoplasms using a monoclonal antibody against a C-terminal T-antigen epitope. Insulinomas have been described in other SV40 transgenic mice, particularly when the SV40 enhancer is not included in the transgene, suggesting that the presence of native SV40 enhancer may ordinarily suppress the expression of T-antigen in pancreatic beta-cells. The somatostatin-cell lesion is unique to the ELSV model; it may be neoplastic or represent a response to the growth and neoplastic changes occurring simultaneously in the exocrine pancreas.

Adenoma, Islet Cell↗
PubMed1990

Cyclosporine inhibition of azaserine-induced atypical acinar cell foci in rat pancreas.

The effects of cyclosporine (CsA), an immunosuppressive agent, on azaserine-induced pancreatic carcinogenesis in rats were investigated using the short-term assays of the quantitation of atypical acinar cell foci. Male Lewis rats at 14 days of age were given a single intraperitoneal injection of azaserine (30 mg/kg). At 25 days of age, the treated rats were weaned and divided into two groups fed either basal diet or the same diet containing 0.011% CsA. Saline-injected rats were also fed the CsA diet. Rats were killed 4 months after azaserine injection and acidophilic and basophilic foci in the pancreas were quantified. The pancreas of the rats given saline injection and maintained on the CsA diet showed no significant histological alterations. The dietary CsA after the injection of azaserine markedly reduced the number of both acidophilic and basophilic foci. It is concluded that addition of CsA to the diet inhibits the growth of initiated cells to form foci in the pancreas of azaserine-treated rats. The experimental model is useful in analyzing the modifying role of this immunosuppressant in the induction and growth of epithelial cell tumors.

Animals↗
PubMed1990

Hormones and receptors in gastrointestinal malignancies.

Receptors for several polypeptide hormones have been demonstrated in cells of the gastrointestinal tract and pancreas. Some of these polypeptides stimulate or inhibit cell division. Therefore, these receptors have been sought in carcinomas arising from these tissues, and several examples have been reported. In some instances, stimulation of tumor growth by the corresponding ligand has been demonstrated or blocked by a receptor antagonist. In experimental carcinogenesis, the incidence of tumors has been influenced by some of the same hormones. Receptors and binding proteins for steroid hormones also have been reported in carcinomas of the pancreas. Manipulation of sex steroid hormones has yielded both inhibition and enhancement of growth of human and rat pancreatic cancers. These observations imply that trophic or growth inhibiting polypeptide and steroid hormones may serve as promoters or inhibitors of carcinogenesis in gastrointestinal organs and may influence the growth of established carcinomas. Receptor blockers may provide a clinical approach for slowing the growth of some gastrointestinal cancers.

Animals↗