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Biomedical subjects

D S Longnecker

Publications and source records attributed to D S Longnecker.

At least 109 records · Page 6Linked to original sources
PubMed1982

Inhibition of pancreatic carcinogenesis by retinoids in azaserine-treated rats.

Chemoprevention by retinoids of the progression of carcinomas induced in rats by azaserine was evaluated. Wistar/Lewis rats were given 15 weekly injections of azaserine, 10 mg/kg, while fed a chow diet; after the completion of carcinogen treatment, they were fed a chow diet supplemented with four different retinoids at the level of 0.5 to 2 mmol/kg diet for 1 year. The incidence of neoplasms was determined by autopsy and histological study. The incidence of pancreatic carcinoma among a male positive control group (azaserine treated, but not retinoid treated) was 42%. The incidence of pancreatic carcinoma among male rats treated with retinoids was: N-2-hydroxyethylretinamide, 6%; N-4-propionyloxyphenylretinamide, 17%; and retinylidene dimedone, 12%. The incidence in rats fed these three retinoids was significantly (p less than 0.05) below the control group incidence. Thus, these three retinoids appeared to be effective in inhibiting the progression of pancreatic carcinomas in the azaserine-induced model. A similar trend was demonstrated in females, but statistical significance was shown only in rats fed N-2-hydroxyethylretinamide. A fourth retinoid, N-4-carboxyphenylretinamide, was more toxic and less effective in chemoprevention. Since retinoids were fed after exposure to carcinogen, the effect was exerted during the postinitiation phase of carcinogenesis. The ratio of invasive pancreatic carcinomas to localized carcinomas (carcinoma in situ) was clearly higher among non-retinoid-treated rats than among those treated with retinoids. This is consistent with retarded progression in the retinoid-treated groups.

Animals↗
PubMed1982

Identification of 7-carboxymethylguanine in DNA from pancreatic acinar cells exposed to azaserine.

Studies were undertaken to determine the identity of an azaserine:DNA adduct. The most probable adduct, 7-carboxymethylguanine, was synthesized. DNA isolated from pancreatic acinar cells treated in culture with [14C]azaserine was hydrolyzed under neutral conditions to liberate N-alkylated purines. The neutral hydrolysate was subjected to high-performance liquid chromatography along with the synthetic standard. One of the radioactive peaks from the treated DNA was found to cochromatograph with 7-carboxymethylguanine in three systems: reverse phase; anion exchange; and ion pair reverse phase. These results suggest that azaserine metabolism in acinar cells results in carboxymethylation of DNA, supporting previously proposed models of azaserine degradation.

Alkylation↗
PubMed1981

A single-dose protocol for azaserine initiation of pancreatic carcinogenesis in the rat.

Previously, the induction of pancreatic carcinogenesis in the rat using azaserine has involved a multiple-dose treatment protocol. The objective of the present study was to determine the effect of multiple azaserine treatments on pancreatic DNA synthesis and to develop a protocol for a single-dose initiation of pancreatic carcinogenesis by azaserine in the rat. Pancreatic DNA synthesis in young rats, which was determined by measuring the amount of [3H]-thymidine incorporation into DNA, was found to be elevated at 4.3 weeks of age and to decrease to a baseline level by 6.3 weeks. Treatment of 4-week-old rats with azaserine resulted in a dose-dependent inhibition of [3H]-thymidine incorporation into both pancreatic and liver DNA. Maximum inhibition was seen at 10 mg/kg body weight. This inhibition was followed by a gradual return of incorporation to normal values over a 48 h period. One week following pretreatment with four weekly injections of azaserine at 30 mg/kg, [3H]-thymidine incorporation into pancreatic and liver DNA was significantly elevated, suggesting that multiple injection protocols caused enhanced DNA synthesis which could have a co-carcinogenic and/or promotional effect. Single-doses of azaserine (10, 30 and 60 mg/kg) given at 7 weeks of age caused the appearance of more atypical acinar cell nodules (AACN) than when given at 5 weeks of age. The most effective dose was 30 mg/kg. Using alkaline elution, we determined that this response was due to the occurrence of more DNA damage in the 7-week-old animals. Thus, these results demonstrate a rationale for the use of single-dose initiation protocols in the pancreas. An effective single-dose protocol for induction of AACN in azaserine-treated rats fed semi-synthetic diet is presented.

Animals↗
PubMed1981

Pancreatic carcinoma in azaserine-treated rats: induction, classification and dietary modulation of incidence.

Pancreatic carcinomas have been induced in Wistar and W/LEW rats by administration of total azaserine doses of 150-520 mg/kg by injection or oral routes over periods of 5-52 weeks. The latent period for development of invasive carcinomas was 1-2 years, but focal abnormalities in acinar cells appear earlier. The incidence of carcinomas varied with total dose, route, and schedule of azaserine administration. The spectrum of histologic patterns of the carcinomas included well and poorly differentiated acinar cell, ductlike, and undifferentiated carcinomas. Rats fed a purified diet developed more pancreatic neoplasms than rats fed a commercial laboratory chow. Selective feeding of these diets during the administration of carcinogen and following completion of carcinogen treatment indicated that the inhibitory effect of chow on pancreatic carcinogenesis was exerted during the postinitiation phas. Supplementation of diet with 0.025% retinyl acetate during the postinitiation phase also inhibited the progression of azaserine-induced lesions in the pancreas.

Adenocarcinoma↗
PubMed1981

Studies of pancreatic nodule induction and DNA damage by D-azaserine.

The ability of the D-isomer of azaserine to induce atypical acinar cell nodules (AACN) in pancreas and to cause DNA damage in pancreas and liver was evaluated. Rats were injected with equivalent doses of D- or L-azaserine and numbers of AACN were counted after 4 months. DNA damage in pancreas and liver of rats treated in vivo, and in pancreatic acinar cells treated in vitro with D- or L-azaserine was determined by alkaline elution. Results show that D-azaserine does not significantly induce AACN in pancreas, nor does it cause extensive DNA damage in comparison with L-azaserine, suggesting that the differential effect of the 2 isomers is related to stereospecificity in either transport or metabolism.

Animals↗
PubMed1981

Studies of DNA damage in rat pancreas and liver by 6-diazo-5-oxo-L-norleucine, ethyl diazoacetate and azaserine.

One hour following intraperitoneal injection of the pancreatic and liver carcinogen azaserine, 10 mg/kg (0.06 mmol/kg), DNA damage is present in both pancreas and liver of Wistar/Lewis rats as determined with alkaline sucrose gradients. Single injections (0.06 mmol/kg) of either of 2 structural analogues of azaserine, 6-diazo-5-oxo-L-norleucine (DON) and ethyl diazoacetate (EDA), do not damage pancreatic or liver DNA. EDA administered at 0.5 mmol/kg damages liver DNA, but not pancreatic DNA. Total radioactivity in pancreas and liver of Wistar rats 1 h after intravenous injection of [14C]azaserine, (10 microCi/kg), is 2.8 and 1.3 times respectively, the level of 14C-activity in pancreas and liver following injection [14C]EDA. Three to four times as much [14C]EDA localizes in the liver of Wistar rats as in the pancreas. Azaserine (0.06 mmol/kg weekly for 6 weeks) induces atypical acinar cell nodules (AACN) in pancreas of Wistar/Lewis rats. DON (0.06 mmol/kg weekly for 6 weeks) induces an elevated incidence, but low number of AACN in pancreas. EDA (0.10 mmol/kg weekly for 6 weeks) does not induce pancreatic AACN.

Animals↗
PubMed1981

The relation of islet amyloid to the clinical type of diabetes.

Islets were evaluated for the presence of amyloid deposits in 169 pancreases removed at autopsy. Islet amyloid occurred in 17 of 142 (12 per cent) of nondiabetics and in 16 of 27 (59 per cent) of diabetics. When diabetics were divided into categories according to clinical severity of disease, the insulin treated diabetics had the highest prevalence (89 per cent), the most diffuse distribution, and the most severe degree of islet amyloidosis. Amyloid was not found in any pancreases from subjects under 40 years of age. Above the age of 40, there was no correlation between aging and prevalence of islet amyloid. There was a significant association between severity of diabetes and prevalence of islet amyloid. The low prevalence of amyloid seen in nondiabetics and the fact that all adult onset, insulin treated diabetics had islet amyloid indicate that a reaction to endogenous insulin may be the basis for the deposition of islet amyloid.

Adolescent↗
PubMed1981

Acute and chronic cisplatin nephropathy in rats.

Cisplatin (cis-dichlorodiammineplatinum-II) is a new class of platinum coordination compounds showing a potent antitumor activity, but it also produces adverse effects on renal function. In this study, cisplatin nephropathy and renal accumulation of platinum were analyzed in rats after acute chronic treatment. A single intraperitoneal dose of cisplatin (6 mg. per kg.) induced marked focal necrosis in the proximal and distal tubules with a maximal lesion on day 7. The tubular damage was localized mainly in the corticomedullary region, where the concentration of platinum was the highest within the kidney. Repeated treatment with cisplatin (1 mg. per kg., intraperitoneally, twice weekly) for 11 weeks resulted in massive tubular basement membranes. Some glomeruli appeared fibrotic, indicating that chronic treatment with cisplatin could cause irreversible renal damage. The results indicated that the toxicity of platinum was probably a major factor for cisplatin nephropathy.

Animals↗
PubMed1981

Promotion by unsaturated fat of azaserine-induced pancreatic carcinogenesis in the rat.

Diet has been shown to modulate the incidence of a wide variety of chemically induced cancers in animals. Various diets fed either during the initiation stage or the postinitiation (promotion) stage of carcinogenesis were evaluated for their ability to modulate the incidence of pancreatic cancer. Male Wistar/Lewis rats were treated with multiple injections of the pancreatic carcinogen, azaserine, during a 6- to 7-week-long initiation phase and were autopsied after a postinitiation phase of 34 or 44 weeks. The following diets were evaluated for their effects on the incidence of pancreatic neoplasms during each stage of carcinogenesis: high saturated fat; two high unsaturated fats (corn oil and safflower oil); low protein; and caloric restricted. A purified control diet was fed during that stage when the test diets were not fed. The incidence of pancreatic adenomas and adenocarcinomas was evaluated by light microscopy. Feeding of the caloric-restricted diet during the initiation phase suppressed the pancreatic neoplasm incidence. None of the ther diets tested had an effect on the incidence of pancreatic cancer during the initiation phase. During the postinitiation phase, both high-unsaturated-fat diets but not the high-saturated-fat diet significantly elevated the pancreatic neoplasm incidence. The low-protein and caloric-restricted diets had no effect on the neoplasm incidence when fed during the postinitiation phase. Thus, diets high in unsaturated fat appear to promote pancreatic carcinogenesis in the azaserine-treated rat while a diet high in saturated fat failed to show a similar degree of enhancement of pancreatic carcinogenesis.

Adenocarcinoma↗
PubMed1981

Dietary modulation of azaserine-induced pancreatic carcinogenesis in the rat.

Because diet has been shown to modulate the incidence of a wide variety of chemically induced cancers in experimental animals, various dietary constituents were evaluated for their ability to modulate the incidence of pancreatic exocrine cancer in male Wistar/Lewis rats given injections of the pancreatic carcinogen, azaserine. Ten different diet regimens were fed. The incidence of pancreatic cancers in rats fed a control diet was compared to that in groups fed diets formulated to evaluate the effect of caloric restriction, high protein, low protein, low fat, cyclopropenoid fatty acids, lipotrope deficiency, high unsaturated fat, and high saturated fat. The incidence of pancreatic adenomas and carcinomas was evaluated by light microscopy. The number of pancreatic neoplasms was reduced in carcinogen-treated groups which were underfed the control diet or fed the diet high in protein. Pancreatic carcinogenesis appeared to be enhanced in two groups which were fed diets containing 20% corn oil, i.e., high in unsaturated fat; whereas, the group fed a diet high in saturated fat had the same incidence of neoplasms as did the group fed the control diet. The pancreatic neoplasms from groups in which the incidence was enhanced by diet showed less evidence of acinar cell differentiation and displayed diverse histological types. In the lipotrope-deficient group, there was a significantly increased incidence of hepatocellular carcinoma; however, a low incidence of liver tumors was encountered in all other dietary groups.

Adenocarcinoma↗
PubMed1980

Focal acinar cell dysplasia in human pancreas.

A series of 108 prospectively collected human pancreata were evaluated histologically for the presence of acinar cell and ductal lesions. Foci of dysplastic acinar cells were present in 44% of the series. Some of the focal acinar cell abnormalities were similar to atypical acinar cell nodules which have been described in carcinogen-treated experimental animals. The incidence of nodules was higher among patients with a history of heavy cigarette smoking than among nonsmokers, and among patients with a history of alcohol abuse than among abstainers. The presence of dysplastic acinar cell nodules in a pancreas seemed unrelated to the presence of cancer in other sites, or diabetes. Ductal epithelial abnormalities were more frequent than focal acinar cell dysplasia.

Adenocarcinoma↗
PubMed1980

Multiple atypical acinar cell nodules of the pancreas.

Although acinar cell nodules of the pancreas have been described in rats given carcinogenic chemicals, similar nodules have not been reported in humans. This report describes two cases of nodular acinar cell lesions in the pancreas in patients who died of insulin secreting islet cell adenoma and of bronchogenic carcinoma. The lesions consisted of multiple nodules that were well demarcated from the surrounding acinar tissue and were composed of zymogen granule containing acinar cells with a pale to pink cytoplasm. The significance of these atypical acinar cell nodules in regard to their being possible precursor lesions of acinar cell carcinoma of the pancreas is discussed.

Adenoma, Islet Cell↗