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S K Clinton

Publications and source records attributed to S K Clinton.

At least 55 records · Page 3Linked to original sources
PubMed1993

Distinct patterns of expression of fibroblast growth factors and their receptors in human atheroma and nonatherosclerotic arteries. Association of acidic FGF with plaque microvessels and macrophages.

Because fibroblast growth factors (FGFs) modulate important functions of endothelial cells (EC) and smooth muscle cells (SMC), we studied FGF expression in human vascular cells and control or atherosclerotic arteries. All cells and arteries contained acidic (a) FGF and basic (b) FGF mRNA. Northern analysis detected aFGF mRNA only in one of five control arteries but in all five atheroma tested, while levels of bFGF mRNA did not differ among control (n = 3) vs. plaque specimens (n = 6). Immunolocalization revealed abundant bFGF protein in control vessels (n = 10), but little in plaques (n = 14). In contrast, atheroma (n = 14), but not control arteries (n = 10), consistently exhibited immunoreactive aFGF, notably in neovascularized and macrophage-rich regions of plaque. Because macrophages colocalized with aFGF, we tested human monocytoid THP-1 cells and demonstrated accumulation of aFGF mRNA during PMA-induced differentiation. We also examined the expression of mRNA encoding FGF receptors (FGFRs). All cells and arteries contained FGFR-1 mRNA. Only SMC and control vessels had FGFR-2 mRNA, while EC and some arteries contained FGFR-4 mRNA. The relative lack of bFGF in plaques vs. normal arteries suggests that this growth factor may not contribute to cell proliferation in advanced atherosclerosis. However, aFGF produced by plaque macrophages may stimulate the growth of microvessels during human atherogenesis.

Arteries↗
PubMed1992

The combined effects of dietary fat, protein, and energy intake on azoxymethane-induced intestinal and renal carcinogenesis.

Two 3 x 3 factorial experiments were conducted to examine the effects of dietary protein (8, 16, and 32% of energy from casein) and dietary fat (12, 24, and 48% of energy from corn oil) on the initiation and promotion of azoxymethane-induced carcinogenesis in rats. For the initiation study, 33 weanling male Sprague-Dawley rats were randomized to each of nine diets fed ad libitum. Azoxymethane was administered s.c. between the fourth to sixth weeks of feeding, providing a total dose of 6 mg/100 g body weight. All rats were subsequently fed a common diet containing 16% energy from protein and 24% energy from fat for an additional 30 to 38 weeks. For the promotion study, all rats were fed a common diet containing 16% of energy from protein and 12% of energy from fat until the completion of azoxymethane administration, when 33 rats were randomized to each of nine diets varying in fat and protein content and fed these diets until sacrifice. Low-protein diets during the initiation phase were associated with increased risk of renal adenocarcinomas (P less than 0.001) and mesenchymal (P = 0.005) malignancies. No other statistically significant relationships were found between the levels of dietary fat or protein and the prevalence of malignant lesions of the small intestine, colon, or kidney in either the initiation or promotion study (although polypoid adenocarcinoma of the colon increased suggestively from 13 to 19 to 26% of rats with increasing dietary protein during initiation). Results of a multiple logistic regression analysis, combining both studies, showed that ad libitum energy intake was significantly associated with intestinal carcinogenesis. The odds of finding an intestinal adenocarcinoma increased by 6.2 +/- 2.6% (SE) for each additional kilocalorie of mean daily ad libitum intake (P = 0.014). The quintile of rats which consumed the least averaged 60 kcal/day, while the most voracious quintile averaged 74 kcal/day. This 14 kcal/day difference in mean ad libitum intake corresponded to more than a doubling (146% increase) of the odds of developing an intestinal adenocarcinoma. These studies suggest that ad libitum energy intake is a critical factor modulating experimental colon carcinogenesis.

Adenocarcinoma↗
PubMed1992

Atherogenic diets enhance endotoxin-stimulated interleukin-1 and tumor necrosis factor gene expression in rabbit aortae.

Cytokine-induced vascular changes may contribute to the atherogenic process. We examined the effect of atherogenic diets on the aortic expression of genes for the cytokines interleukin-1 alpha and beta and tumor necrosis factor alpha. Male New Zealand White rabbits were fed one of the following diets for 10 wk: nonpurified diet, a semipurified diet with 10% corn oil, a semipurified diet with 1% corn oil and 9% partially hydrogenated coconut oil, or the 9% coconut oil diet supplemented with either 0.1, 0.3 or 0.9% added cholesterol (n = 6/group). At 10 wk, 3 rabbits per group received lipopolysaccharide (200 micrograms/kg) intravenously. After 1.5 h the rabbits were killed and their aortae removed and analyzed. Histologic examination showed that the 0.3% and 0.9% cholesterol-fed rabbits developed appreciable aortic lesions. Diet had no major effect on the basal levels of aortic cytokine mRNA as determined by polymerase chain reaction analysis of DNAs. However, aortic tissue from rabbits fed 0.3% and 0.9% cholesterol diets showed significantly enhanced lipopolysaccharide-evoked levels of mRNA encoding interleukin-1 alpha (392 +/- 91 for saturated fat vs. 759 +/- 191 and 800 +/- 120 fmoles/reaction for 0.3% and 0.9% cholesterol), interleukin-1 beta (99 +/- 10 vs. 353 +/- 80 and 355 +/- 86) and tumor necrosis factor alpha (195 +/- 15 vs. 594 +/- 78 and 667 +/- 97). Extracts of aortae from rabbits injected with lipopolysaccharide contained interleukin-1 and tumor necrosis factor alpha activity but differences in biological activity due to diet were not detectable at the 1.5 h time point (chosen for maximal mRNA expression). Increased local cytokine gene expression in response to acute stimulus might influence the evolution of the vascular response to diets rich in cholesterol and saturated fats.

Animals↗
PubMed1992

Cytokines as mediators of vascular pathology.

Interactions between leukocytes and intrinsic vascular wall cells characterize many inflammatory reactions and contribute importantly to the pathogenesis of many vascular diseases. In view of this intimate involvement of leukocytes in vascular pathology it is important to understand the signals that recruit and activate leukocytes locally in regions of vascular pathology. It is also desirable to delineate the mechanisms by which leukocytes influence the behavior of intrinsic vascular wall cells in ways which may contribute to vascular lesion formation. Mediators elaborated by leukocytes include small molecules including lipid-derived mediators such as prostanoids, leukotrienes, and platelet activating factor. Leukocytes can also produce protein mediators including those currently classified as cytokines. The cytokines, protein mediators involved in inflammation and control of the immune response, derive from all classes of leukocytes studied. Local cytokine networks may orchestrate complex programs of expression of functions of leukocytes and endothelial and smooth muscle cells involved in vascular homeostasis and pathology. Our laboratory has been interested in hyperplastic arterial diseases including atherosclerosis and restenosis following angioplasty treatment of obstructive atherosclerosis. Definitive evidence for roles of cytokines in the pathogenesis of these syndromes are lacking. However, various in vitro and in vivo studies have furnished sufficient information to permit formulation of rather detailed hypotheses or models. In hypercholesterolemic rabbits vascular cell adhesion molecule-l (VCAM-l) may participate in initial monocyte recruitment to prelesional areas of arterial endothelium. Other adhesion molecules including Intercellular adhesion molecule-l (ICAM-l) may also participate in monocyte adhesion to arterial endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

A cascade model for restenosis. A special case of atherosclerosis progression.

BACKGROUND: Restenosis presently limits the long-term success of percutaneous transluminal coronary angioplasty (PTCA) and allied treatments of atheroma. Current views of the pathophysiology of restenosis fail to explain certain important clinical features: Thrombosis, often invoked as a cause of smooth muscle proliferation, wanes before intimal thickening peaks. Prolonged antithrombotic therapy does not eliminate restenosis after PTCA. Furthermore, only a minority of angioplastied lesions develop clinically significant restenosis. METHODS AND RESULTS: We propose a cytokine-growth factor cascade mechanism of restenosis pathobiology that could explain these features of human restenosis. According to this model, PTCA would produce acute local thrombosis and/or mechanical injury that triggers cytokine/growth factor gene expression by resident macrophages and smooth muscle cells. This early acute generation of cytokines could evoke a secondary growth factor and cytokine response that might establish a positive, self-stimulatory autocrine and paracrine feedback loop that would serve to amplify and sustain the proliferative response. This multistage schema would account for the lag between injury and restenosis and the failure of chronic antithrombotic therapy to prevent this process. Human atheromata contain variable numbers of macrophages. The macrophage content of a particular lesion could determine in part propensity to develop restenosis after angioplasty, explaining why all lesions do not develop this process. CONCLUSIONS: Several experimental observations support this novel mechanistic model. Leukocytes and smooth muscle cells express genes for cytokines and growth factors, and products of coagulation and thrombosis can activate mononuclear phagocytes. Cytokines and growth factors often augment their own gene expression and induce one another, providing a potential intralesional amplification loop. Experimental atheroma and advanced human atherosclerotic lesions do not express high levels of growth-stimulatory cytokines such as interleukin-1 or tumor necrosis factor in the basal state but exhibit inducible expression in response to an injurious stimulus. Thus, cascades of autocrine or paracrine mediators whose expression is triggered by vascular injury might contribute to deranged smooth muscle behavior during restenosis.

Angioplasty, Balloon, Coronary↗
PubMed1992

Cytokines and growth factors in atherogenesis.

The development of laboratory techniques for the culturing of vascular endothelial and smooth-muscle cells during the 1970s, followed by the rapid advances in molecular and cell biology during the 1980s, provided the foundation for the identification of growth factor and cytokine networks involved in maintenance of the normal vasculature as well as participating in diverse pathologic processes involving blood vessels. Vascular cells can produce and respond to a vast array of biochemical messengers that control cell replication, differentiation, and many specific cell functions. Investigators are beginning to explore the changes in the patterns of messengers exchanged between the vascular cells and infiltrating leukocytes during the initiation and progression of atherosclerosis. A variety of in vitro and in vivo studies have indicated that growth factors and cytokines that mediate the critical processes of inflammation and wound healing also play a central role in vascular disease. Indeed, many view atherosclerosis as the result of excessive or prolonged chronic inflammation and wound healing in response to diverse injurious stimuli to cells of the vessel wall. Vascular injury may result from many varied and interacting forces, including nutritional and metabolic abnormalities such as hyperlipidemias or elevated homocysteine, mechanical forces associated with hypertension, exogenous toxins including those found in cigarette smoke, abnormally glycated proteins associated with diabetes mellitus, oxidatively modified lipids or proteins, and, possibly, viral infections. Ultimately, a greater understanding of the activated cytokine and growth factor networks within the vascular wall following injury and during atherogenesis will allow clinical scientists to identify steps susceptible to therapeutic intervention using recombinant cytokines, antibodies, soluble receptors, or receptor antagonists. Other therapeutic strategies may involve the transfection of specific genes, which may inhibit atherosclerosis, into vascular cells at sites prone to lesion formation.

Animals↗
PubMed1992

Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis.

The infiltration of monocytes into the vascular wall and their transformation into lipid-laden foam cells characterizes early atherogenesis. Macrophages are also present in more advanced human atherosclerotic plaques and can produce many mediators that may contribute to lesion formation and progression. Macrophage colony-stimulating factor (MCSF) enhances the proliferation and differentiation of monocyte progenitors and is required for the survival and activation of mature monocytes and macrophages. The authors therefore examined the expression of the MCSF gene in cultured human vascular endothelial (EC) and smooth muscle cells (SMC) as well as in atheromatous lesions from rabbits and humans. Growth arrested EC and SMC contain a low level of MCSF mRNA. Bacterial lipopolysaccharide (LPS), recombinant human interleukin-1 alpha (IL-1 alpha) or tumor necrosis factor alpha (TNF alpha) induced MCSF mRNA accumulation in a concentration-dependent manner in both EC and SMC. These stimuli induced large increases in MCSF mRNA with peak induction between 4-8 hours after treatment. LPS, IL-1 alpha, and TNF alpha stimulated EC and SMC also showed increased fluorescent antibody staining for MCSF protein and released immunoreactive MCSF in a time-dependent manner. In contrast, phorbol 12-myristate 13-acetate (PMA) was a less potent inducer of MCSF gene expression and iron-oxidized low-density lipoproteins (ox-LDL) did not increase consistently MCSF mRNA or the synthesis and secretion of immunoreactive protein. Northern analysis of mRNA isolated from the atheromatous aorta of rabbits fed a 1% cholesterol diet for 10 weeks showed elevated MCSF mRNA compared with controls. Immunostaining of atheromatous arterial lesions of rabbits demonstrated MCSF protein in association with intimal SMC as well as macrophages. Furthermore, polymerase chain reaction (PCR) analysis of MCSF mRNA in human atheromata showed higher levels than found in nonatherosclerotic arteries and veins. Since the authors found no mRNA for the MCSF receptor, c-fms, in cultured EC or SMC macrophages are likely the primary target for MCSF within atheromatous vessels. The authors therefore investigated the effects of MCSF on monocyte functions related to foam cell development. Treatment of cultured human monocytes with recombinant human MCSF (10(3) U/ml, 72 hr) led to the accumulation of mRNA for the acetyl-LDL (scavenger) receptor and apolipoprotein E (apo E). These studies establish that vascular EC and SMC produce substantial MCSF in response to a variety of stimuli. The local production of MCSF during atherogenesis may contribute to macrophage survival and proliferation or activate specific macrophage functions such as expression of the scavenger receptor and secretion of apo E.

Animals↗
PubMed1991

Dietary protein and chronic toxicity of 1,2-dimethylhydrazine fed to mice.

1,2-Dimethylhydrazine-HCl (DMH-2HCl) is derived from the natural toxin cycasin, and is extensively used to induce cancers in experiments with rodents. We examined the toxicity of DMH-2HCl, incorporated into purified diets varying in protein, to determine concentrations compatible with long-term survival in B6C3H1 mice. Initial studies showed single-dose oral LD50 values (95% confidence intervals) of 26 (18-32) mg DMH-2HCl/kg body weight for males, and 60 (53-65) for females. A 6-wk study was performed with diets containing 10 or 40% soybean protein with doses of 0, 11.25, 22.5, 45, 90, and 180 mg DMH-2HCl/kg diet. All mice fed the highest dose were removed from the study due to severe toxicity. Declines in food consumption and body weight occurred in both sexes, accelerated with increasing log(DMH) dose, and were substantially more severe in groups fed 10% protein. A 5-mo study was subsequently performed with male mice fed 10 or 40% protein diets containing doses of 0, 15, 30, or 45 mg DMH-2HCl/kg diet. In this longer study, dose-related declines of food intake and body weight were also more pronounced with 10% protein. Histopathologic examination of samples from 29 organs/tissues revealed hepatic changes most commonly, and these were more severe at higher DMH levels. Lesions ranged from focal centrilobular hepatocellular necrosis to severe toxic hepatitis, associated with lobular disorganization and hepatocellular hypertrophy. Frequent dose-dependent lesions were also found in kidneys, adrenals, and heart. Renal changes included focal subcapsular fibrosis with atrophy, and hyperplasia of the tubular epithelium. Adrenal cortical hypertrophy was noted at the two highest DMH doses. Focal cardiac myocytolysis was also noted at high DMH doses. Renal damage occurred only rarely in the absence of liver pathology, and adrenal hypertrophy only rarely without renal damage. Cardiac myocytolysis was found in 14% of mice without hepatic, renal, or adrenal damage, but in 62% of those with lesions in each of those organs. No evidence of gastrointestinal toxicity was observed. Hepatic, renal, and adrenal lesions were more frequent and severe in mice fed the low-protein diet. The protective effect of high protein was DMH-dose dependent. The lower doses in these studies could be used to investigate effects of diet, cocarcinogens, or chemopreventative agents on carcinogenesis resulting from chronic, low-level dietary exposure to DMH.

1,2-Dimethylhydrazine↗
PubMed1991

Interleukin-1 gene expression in rabbit vascular tissue in vivo.

Cultured human vascular endothelial and smooth muscle cells express interleukin-1 (IL-1) genes when exposed to bacterial lipopolysaccharides (LPS) and a variety of inflammatory mediators. Local production of IL-1 may contribute to the pathogenesis of various vascular diseases. Therefore the ability of intact vascular tissue to accumulate IL-1 mRNA and synthesize de novo biologically active IL-1 protein was examined. Escherichia coli LPS (10 micrograms/kg) was administered intravenously to adult rabbits and total RNA was isolated from aortic tissue at various times after LPS injection. In saline-injected rabbits, RNA extracted from the thoracic aorta contained little or no IL-1 message detected by Northern analysis using IL-1 alpha and beta cDNA probes cloned from an LPS-stimulated rabbit splenic macrophage library. Lipopolysaccharide treatment promptly induced transient accumulation of mRNA for IL-1 alpha and IL-1 beta within the aorta (maximal 1-hour after injection). Short-term organoid cultures of rabbit aorta exposed to LPS in vitro synthesized immunoprecipitable IL-1 alpha protein. Extracts of aortic tissue excised 1.5 to 3.0 hours after intravenous LPS administration contained immunoreactive and biologically active IL-1 alpha. Anti-rabbit IL-1 alpha antibody neutralized the biologic activity (more than 90%). Microscopic and immunohistochemical studies did not disclose adherent or infiltrating macrophages in rabbit aorta at the time of maximal IL-1 mRNA accumulation after LPS administration (1.5 hours), indicating that intrinsic vascular wall cells rather than mononuclear phagocytes probably account for the IL-1 activity induced by LPS. In addition, aortic tissue from rabbits fed an atherogenic diet showed an enhanced ability to accumulate IL-1 alpha and beta mRNA and produce immunodetectable protein in response to LPS administration. These studies demonstrate inducible IL-1 gene expression in rabbit vascular tissue in vivo and support a local role for this cytokine in vascular pathophysiology.

Animals↗
PubMed1989

Wheat bran and the induction of intestinal benzo(a)pyrene hydroxylase by dietary benzo(a)pyrene.

The mucosa of the intestine responds to polycyclic aromatic hydrocarbons (PAH) with the rapid induction of benzo(a)pyrene hydroxylase (BPH). Studies were conducted to determine if dietary fiber would reduce exposure of the intestine to dietary benzo(a)pyrene (BP) as indicated by intestinal BPH activity. In all studies, female Sprague-Dawley rats were fed a fiber-free purified diet for 7 d, whereupon they were switched to experimental diets for 48 h. After 48 h their small intestinal mucosa was assayed for BPH activity. Diets for the initial study contained 0, 100, 400, 800, or 1200 mg BP/kg diet, each with and without 10% soft white wheat bran. Enzyme induction with 100 and 400 mg BP/kg diet was partially inhibited by bran, but with higher concentrations of BP there was no protective effect. The inhibition in BP-induced intestinal BPH activity was observed with 10% wheat bran but not with 3.3 or 6.6%. Subsequent studies showed no significant inhibition in BPH induction with cellulose or lignin, whereas all forms of wheat bran (hard red, soft white, or finely ground soft white) caused significant inhibition. In the final study, a diet containing charcoal-broiled beef, a known source of PAH, was compared with diets containing raw beef or soybean protein, each with and without 10% soft white wheat bran. BPH activity remained low with raw beef and soybean protein whether or not fiber was added. However, intestinal BPH activity was raised ninefold by charcoal-broiled beef. The addition of bran reduced BPH activity to 65% of that observed with the fiber-free, charcoal-broiled beef diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Hepatic and intestinal drug-metabolizing enzymes and the tissue distribution and excretion of 14C-7,12-dimethylbenz[a]anthracene in rats fed diets varying in fat concentration.

Diets containing 12 or 48% of calories from corn oil were fed to weanling Sprague-Dawley female rats for 28 days. Hepatic cytochrome P-450 content was higher with the high-fat diet, but the activities of cytochrome P-450 reductase, cytochrome c reductase, benzo[a]pyrene hydroxylase (BPH), and uridine-5'-diphosphoglucuronic acid (UDPGA) transferase were unchanged. There were no differences in small intestinal cytochrome P-450 or BPH attributable to diet. Additional rats given an oral dose of 14C-7,12-dimethylbenz[a]anthracene (14C-DMBA) after 28 days of feeding showed no effects of diet on the cumulative daily excretion of radioactivity from 14C-DMBA in the urine or feces over 72 h. However, rats fed the high-fat diet showed greater concentrations of radioactivity in the liver, kidney, adrenal, pituitary, breast, and adipose tissue at 4 h after dosing when compared to rats fed low-fat diets. The transiently higher tissue concentrations of 14C-DMBA in rats fed a high-fat diet prior to DMBA administration correlate with the enhancement of mammary cancer induction seen when high-fat diets are fed prior to administration of this carcinogen.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Effects of ammonium acetate and sodium cholate on N-methyl-N'-nitro-N-nitrosoguanidine-induced colon carcinogenesis of rats.

This study was conducted to determine the effects of ammonium acetate alone or in combination with sodium cholate upon N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced colon carcinogenesis in rats. Ammonia, acetate, and deconjugated bile acids are produced by microbial enzymes in the gastrointestinal lumen. One hundred twenty male Sprague-Dawley rats, weighing 196 +/- 2 g at 8 wk of age, were given four intrarectal doses of MNNG (2 mg/dose) over 2 wk. They were then randomly assigned among four treatment groups, each containing 30 rats. The groups were arranged in a 2 x 2 factorial design and given intrarectal infusions of the agents under study in 0.3 ml of double-distilled water 3 times weekly for 52 wk beginning 4 wk after the initial MNNG treatment. The experimental treatments were: double-distilled water as control; ammonium acetate (24.8 mg of ammonia); sodium cholate (2 mg of cholic acid); and a combination of ammonium acetate and sodium cholate. Ammonium acetate treatment increased the number of rats with fecal blood 4-fold after 56 wk, and this was associated with a higher incidence of adenocarcinomas with a polypoid morphology. The incidence and total number of carcinomas in situ (high grade dysplasia) increased with ammonium acetate treatment. Ammonium acetate increased the total number of adenocarcinomas. Sodium cholate had no significant main effects on the incidence or morphology of colon lesions. The data support the conclusion that ammonium acetate treatment acted as a promoting agent in MNNG-induced colon carcinogenesis.

Acetates↗
PubMed1988

The combined effects of dietary protein and fat intake during the promotion phase of 7,12-dimethylbenz(a)anthracene-induced breast cancer in rats.

A 3 X 3 factorial experiment was conducted to examine the effects of dietary protein (8, 16 or 32% of energy from casein) and dietary fat (12, 24 or 48% of energy from corn oil) on the promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinogenesis in rats. A purified diet with protein and fat supplying 16 and 24% of energy, respectively, was fed to 360 rats. After 4 wk each rat received DMBA (20 mg/kg) via gastric intubation. Forty rats were then randomly assigned to each of the nine dietary treatments for 28 wk. We observed no effects of protein or interactions between protein and fat on mammary tumorigenesis. At necropsy, rats fed diets containing 12, 24 and 48% of energy from corn oil following DMBA administration showed tumor prevalences of 53, 60 and 70% with 109, 127 and 140 total tumors, respectively. Linear logistic statistical modeling indicated that each doubling of dietary fat concentration multiplied the odds of finding a tumor of any histologic type at necropsy by 1.52. Dietary fat had no significant effects on the prevalence of adenomas or fibroadenomas, whereas those fed corn oil at 12, 24 and 48% of dietary energy showed adenocarcinoma prevalences of 34, 41 and 52% with total adenocarcinoma counts of 66, 75 and 96, respectively. Our results suggest that increasing dietary fat enhanced the promotion of DMBA-induced breast carcinogenesis over a wide range of protein intake.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Growth of Dunning transplantable prostate adenocarcinomas in rats fed diets with various fat contents.

The effects of dietary fat concentration (5 vs. 20% corn oil, 0.5 vs. 20% corn oil and fat-free vs. 20% corn oil) on the growth of the Dunning R3327-H (hormone-sensitive, well-differentiated, slow-growing) and R3327-150 (hormone-insensitive, anaplastic, rapidly growing) transplantable prostate tumor sublines were studied in Copenhagen x Fisher F1 male rats. Rats fed 5 vs. 20% corn oil or 0.5 vs. 20% corn oil showed no differences in either R3327-H or R3327-150 tumor growth. Fat-free diets had no effect on the growth of R3327-150 tumors. However, the mean weight of the R3327-H tumor at necropsy, 16 wk after implantation, was reduced by 40% in rats fed a fat-free diet compared with 20% corn oil (P less than 0.05). Energy intake, weight gain and the weight of the pituitary and prostate glands in rats bearing either tumor was lower in rats fed the fat-free diet than in those fed the 20% corn oil diet. There were no differences in serum prolactin, pituitary prolactin or serum testosterone associated with dietary fat concentration in any study. In summary, no differences in transplantable prostate tumor growth were seen over a wide range of lipid intake (0.5-20%), although a fat-free diet reduced the growth of the R3327-H prostate adenocarcinoma.

Adenocarcinoma↗
PubMed1987

Lymphocyte activation, cell-mediated cytotoxicity and their relationship to dietary fat-enhanced mammary tumorigenesis in C3H/OUJ mice.

The effects of dietary soybean oil (SBO) concentration (5 vs. 20% by weight) on mammary tumorigenesis, mitogen-induced blastogenesis, cell-mediated cytotoxicity and serum and lymphocyte fatty acid composition were studied in C3H/OUJ female mice. Weanling mice fed 20% SBO for 9 mo had a higher incidence (89 vs. 65%) and greater average size (2.9 vs. 1.9 g) of mammary tumor virus type S breast tumors than mice fed 5% SBO. The response of isolated splenocytes to the T-cell mitogens concanavalin A and phytohemagglutinin was 20-25% lower in mice fed 20% SBO than in mice fed 5% SBO for 20 wk. There was no effect of SBO concentration on the splenocyte response to lipopolysaccharide E55:B5, a B-cell mitogen, or to pokeweed mitogen, and B- and T-cell mitogen. Cell-mediated cytotoxicity to allogenic P815 tumor cells was 20% lower in mice fed 20% SBO than in mice fed 5% SBO for 12 wk. The lower cell-mediated immunity associated with 20% SBO was not due to changes in the fatty acid composition of the two major splenocyte membrane phospholipids, phosphatidylcholine and phosphatidylethanolamine. However, serum levels of linoleic acid were higher in mice fed 20% SBO. Raising dietary SBO from 5 to 20% by weight was associated with increased mammary tumorigenesis, reduced T-cell blastogenesis and lower cell-mediated cytotoxicity.

Animals↗
PubMed1986

Effects of dietary protein, fat and energy intake during an initiation phase study of 7,12-dimethylbenz[a]anthracene-induced breast cancer in rats.

A factorial experiment was conducted to examine the effects of dietary protein (8, 16, 32% of energy from casein) and dietary fat (12, 24, 48% of energy from corn oil) on the initiation of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast carcinogenesis in rats. Forty weanling female Sprague-Dawley rats were assigned to each of nine diets fed ad libitum. After 4 wk each rat received DMBA (20 mg/kg) via gastric intubation. For an additional 22 wk after carcinogen administration all rats consumed a diet containing 16% of dietary energy from protein and 24% from fat. Dietary fat, protein and ad libitum energy consumption exhibited statistically significant effects on final tumor prevalence, but interactive effects were not found. At necropsy, rats fed corn oil at 12, 24 and 48% of energy prior to DMBA administration showed tumor prevalences of 58, 58 and 85% with 116, 153 and 231 total tumors, respectively. The data indicate a significant nonlinear effect of dietary fat. Corresponding numbers for rats fed casein at 8, 16 and 32% of energy prior to DMBA were prevalences of 79, 65 and 59%, with total tumor counts of 194, 144 and 162. Higher dietary protein during the initiation phase was associated with a significant reduction in tumor prevalence, which was most striking between 8 and 16% of energy from protein. In addition, results of multiple logistic regression showed that tumorigenesis was increased with greater ad libitum energy intake. The odds of a tumor at necropsy were multiplied by 1.19 for each kilocalorie increase in ad libitum energy intake averaged over the post-DMBA phase of the experiment. An additional six weanling rats fed each diet for 4 wk were killed for assay of hepatic carcinogen metabolizing enzymes at the time corresponding to DMBA administration in the initiation experiment. Both protein and fat showed independent effects on the activity of several enzymes. However, enzyme activity did not suggest a unifying mechanism whereby these nutrients influence DMBA-induced mammary carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Plasma amino acids and excretion of protein end products by mice fed 10 or 40% soybean protein diets with or without dietary benzo[a]pyrene or 1,2-dimethylhydrazine.

The effects of two carcinogens benzo[a]pyrene (BP) and symmetrical 1,2-dimethylhydrazine dihydrochloride (DMH), on plasma amino acid concentrations and on excretion of lipids and nitrogenous metabolites were studied in 7- to 8-wk-old male and female B6C3F1 mice. BP and DMH were fed at concentrations of 0.3125 and 0.0225 g/kg, respectively, in purified diets containing 10 or 40% soybean protein. Nutritional balances were measured over a 7-d period after 7 d of acclimatization. Females excreted less urea and more NH3 than males. Urinary urea-nitrogen, NH3, allantoin, uric acid and total urinary nitrogen were consistently higher in mice fed 40% protein than in those fed 10% protein. The increases in total and NH3 nitrogen paralleled the increase in nitrogen intake. Nitrogen of urea rose more, while that of allantoin and uric acid rose less, than nitrogen intake. Fecal lipid excretion, as a percentage of intake, was consistently higher in mice fed the 40% protein diets than in mice fed 10% protein. Plasma glycine and branched-chain amino acids were higher, but citrulline was lower, when the 40% protein diet was fed. Body weight gain was higher when the 10% protein diet was fed with BP than without it, but BP made no apparent difference in weight gain when the 40% protein diet was fed. BP interacted with dietary protein to influence the excretion of nitrogenous metabolites. In addition, BP feeding produced numerous BP X sex and BP X protein interactions for plasma amino acid concentrations. Compared to controls, feed intake and weight gain were, respectively, 8 and 61% lower in DMH-fed animals during wk 1, but no differences in intake or weight gain were found during wk 2. In contrast to BP, DMH had no significant effects on urinary or fecal nitrogen metabolites, except that urinary uric acid (relative to nitrogen intake) was 9% higher in DMH-fed mice than in controls. DMH-fed mice had 43% higher serum glutamate and 6% lower glutamine than controls.

1,2-Dimethylhydrazine↗