Dietary fat and energy modulation of biochemical events in tumor promotion.
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9,10-Dimethyl-1,2-benzanthracene↗
Biomedical subjects
D F Birt
Publications and source records attributed to D F Birt.
High-fat diet blocks the inhibition of skin carcinogenesis and reductions in protein kinase C by moderate energy restriction.
The aim of this investigation was to determine the impact of dietary energy restriction (ER) with control (C) and high-fat (HF) diets on two-stage skin carcinogenesis and on the expression of specific isoforms of protein kinase C (PKC). Skin carcinogenesis was initiated on SENCAR mice with 10 nmol of 7,12-dimethylbenz[a]anthracene (DMBA) in 0.2 mL of acetone and then promoted with twice weekly treatments of 3.2 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) in 0.2 mL of acetone for 18 wk. The experimental diets fed during TPA treatment and for 10 wk after the last TPA treatment were formulated with C (10% calories from fat) and HF (42% calories from fat) levels for freely fed groups. These diets were restricted by 20% (20% ER/C and 20% ER/HF) and by 40% (40% ER/C and 40% ER/HF). Papilloma incidence was reduced in the mice fed the 20% ER/C, 40% ER/C, and 40% ER/HF diets in comparison with the C, HF, and 20% ER/HF groups. Carcinoma incidence was also reduced in these groups. PKC alpha and zeta were assessed by western blot analysis in the epidermises of mice pre-fed the six diets for 8-10 wk (without DMBA or TPA treatment). PKC alpha was reduced in the particulate fraction by 32-44% in the 20% ER/C, 40% ER/C, and 40% ER/HF groups (P < 0.005). PKC zeta was reduced by 24-31% in the cytosol of mice fed the 20% ER/C diet and in the particulate fraction of mice fed the 40% ER/C diet (P < 0.05). The HF diet was able to block the inhibition of skin carcinogenesis and the reduction in the expression of PKC in the epidermis by 20% ER but not by 40% ER.
Animals↗
Influence of vehicle, distant topical delivery, and biotransformation on the chemopreventive activity of apigenin, a plant flavonoid, in mouse skin.
PURPOSE: This study was designed to (a) establish a short-term in vivo system to evaluate topical formulations of apigenin, (b) determine whether apigenin should be topically delivered to the local skin tissue or systemic circulation, (c) investigate if biotransformation was involved in apigenin's chemopreventive activity. METHODS: The effect of topical applied apigenin in acetone/DMSO (A/D, 9:1) on the promotion of skin tumorigenesis was studied. The influence of apigenin in DMSO, A/D (4:1), and propylene glycol/DMSO (PG/D, 4:1) on 12-O-tetradecanoylphorbol-13 acetate (TPA) induced ornithine decarboxylase (ODC) activity was compared. Distant topical delivery of apigenin was conducted on abdominal skin and ODC activity was monitored in dorsal skin. Potential glucuronidation/sulfation of apigenin in intact skin was assessed by measuring isolated apigenin before and after enzyme hydrolysis with glucuronidase/sulfatase. The epidermal extracts from apigenin-treated SENCAR mice were analyzed for metabolites by HPLC. RESULTS: Apigenin (5 mumol) in A/D did not significantly reduce skin tumor incidence in contrast to previous data with DMSO. Inhibition of TPA-induced ODC by apigenin in three vehicles was in the order of DMSO > A/D > PG/D. TPA-induced ODC in dorsal skin was not inhibited by apigenin delivered from abdominal skin. The quantity of apigenin recovered from epidermal extract was not different before and after beta-glucuronidase/sulfatase treatment. Metabolites were not observed in the HPLC profiles of epidermal extracts from apigenin treated mice. CONCLUSIONS: (a) The short-term TPA-induced ODC was validated for evaluating topical formulations of apigenin. (b) Topical delivery of apigenin should target the local skin tissue. (c) Glucuronidation/sulfation appeared not to be involved in apigenin's chemopreventive activity.
9,10-Dimethyl-1,2-benzanthracene↗
In vivo and in vitro percutaneous absorption of cancer preventive flavonoid apigenin in different vehicles in mouse skin.
PURPOSE: In vivo and in vitro percutaneous absorption of apigenin was investigated in three vehicles previously used in cancer prevention studies to determine the drug delivery properties for optimal chemo-preventive activity. METHODS: In vivo percutaneous absorption of apigenin on SENCAR mice was studied with DMSO and acetone/DMSO (A/D, 4:1) vehicle. In vitro percutaneous absorption studies used whole mouse skin, without subcutaneous fat, mounted on Franz diffusion cells with 37 degrees C Dulbecco's phosphate-buffered saline as the receptor fluid. The skin was treated with [G-3H]-apigenin in DMSO, A/D (4:1), or propylene glycol/DMSO (PG/D, 4:1). RESULTS: Apigenin uptake by epidermal cells and distribution in epidermis following in vivo topical treatment in two vehicles was in the order of A/D > DMSO, while apigenin distribution in dermis and subcutaneous fat was not different between DMSO and A/D. Total apigenin absorption in mouse skin in vitro was in the order of A/D > DMSO > PG/D. However, apigenin sub-tissue distribution within epidermis determined by tape-stripping and by determination of apigenin in dermal and epidermal tissue indicated that DMSO delivered more apigenin into viable epidermis than A/D while A/D deposited more apigenin in the stratum corneum. Apigenin absorption in mouse skin with DMSO or A/D showed saturation kinetics while apigenin in PG/D showed very low absorption initially and non-saturated absorption in a period of 6 hr. HPLC-scintillation profiles of in vitro samples showed no evidence of apigenin metabolism in mouse skin. CONCLUSIONS: Delivering apigenin into viable epidermis appears to be a necessary property for an apigenin formulation to be effective in skin cancer prevention.
Acetone↗
Effects of voluntary physical exercise on high-fat diet-promoted pancreatic carcinogenesis in the hamster model.
We examined the effect of voluntary physical exercise (running wheels) on pancreatic carcinogenicity of N-nitrosobis-(2-oxopropyl) amine (BOP) in groups of female Syrian hamsters fed a high-fat (HF) diet in which corn oil was 24.6% of the diet or a low-fat (LF) diet in which corn oil was 4.5% of the diet. Each group was divided into an exercising (EX) group (LF-EX and HF-EX) and a sedentary (S) group (LF-S and HF-S). All hamsters were treated with BOP (20 mg/kg body wt) weekly for two weeks beginning four weeks after the experimental diets, which were fed from weaning. A modified glucose tolerance test was performed before the BOP injections and then again at 20 and 40 weeks, and the levels of glucose, insulin-like growth factor I, and insulin were determined in the plasma samples. At the end of the experiment, serum levels of lipid metabolites were also examined in six hamsters from each group. The experiment was terminated 44 weeks after the BOP treatment. Pancreatic ductal/ductular adenocarcinoma incidence was significantly higher in hamsters fed the HF diet (HF-S and HF-EX) than in those fed the LF diet (LF-S and LF-EX). In all groups, glucose and insulin-like growth factor I levels remained within the normal range throughout the experiment, whereas insulin and lipid metabolite levels were significantly elevated in all hamsters fed the HF diet (HF-S and HF-EX). Exercise significantly reduced the insulin level in the group fed the HF diet but did not influence the cancer burden, possibly by the generation of reactive lipid metabolites. Overall, the results showed that voluntary physical exercise does not influence the promotional action of the HF diet on pancreatic carcinogenesis in hamsters. This action could be attributed to the ability of the HF diet to increase the secretion of insulin, which has a growth-promoting and mitogenic effect on pancreatic cells, and to the effect of an HF diet or physical exercise in producing excess free radicals.
Adenocarcinoma↗
The chemopreventive flavonoid apigenin induces G2/M arrest in keratinocytes.
Apigenin is a plant flavonoid which has been shown to significantly inhibit UV-induced mouse skin tumorigenesis when applied topically, and may represent an alternative sunscreen agent in humans. We have investigated the molecular mechanism(s) by which apigenin inhibits skin tumorigenesis. Initial studies examined the effects of apigenin on the cell cycle. DNA flow cytometric analysis indicated that culturing cells for 24 h in medium containing apigenin induced a G2/M arrest in two mouse skin derived cell lines, C50 and 308, as well as in human HL-60 cells. The G2/M arrest was fully reversible after an additional 24 h in medium without apigenin. We investigated the effects of apigenin on cyclin B1 and p34cdc2, since cyclin B1/p34cdc2 complexes regulate G2/M progression. Western blot and immune complex kinase assays using whole cell lysates from 308 and C50 cells treated for 24 h with 0-70 microM doses of apigenin demonstrated that apigenin treatment did not change the steady-state level of p34cdc2 protein, but did inhibit p34cdc2 H1 kinase activity in 308 cells. Western blot analysis showed that apigenin treatment of C50 cells and 308 cells inhibited the accumulation of cyclin B1 protein in a dose-dependent manner. The apigenin levels detected in cultured keratinocytes were relevant to those detected in epidermal cells of Sencar mice treated with tumor inhibitory doses of apigenin. In conclusion, we present evidence that apigenin induces a reversible G2/M arrest in cultured keratinocytes, the mechanism of which is in part due to inhibition of the mitotic kinase activity of p34cd2, and perturbation of cyclin B1 levels.
Animals↗
Diet intervention for modifying cancer risk.
Considerable evidence suggests that dietary differences between populations account for a significant proportion of the variation in cancer occurrence in different parts of the world. A major problem has been identifying the particular dietary components which predispose or protect individuals against cancer. For example, the high rates of breast and colon cancer in the United States have been associated with numerous dietary patterns including high fat, high dietary energy, and low fruit and vegetable intakes. Our laboratories have attempted to identify mechanisms whereby diet may modify cancer and it is anticipated that future studies will determine which of these potential mechanisms may be relevant in humans. A promising lead in understanding the mechanism of high dietary fat/high dietary energy promotion of cancer was the impact of these diets on cellular protein kinase C (PKC). PKC is important in cellular signaling events which are critical to tumor promotion. Our studies demonstrated increased PKC activity and/or protein expression observed in epidermis and pancreatic epithelial cells of rodents fed high fat/energy diets. The inverse association between cancer at a number of sites and fruit and vegetable intake may be due to both micronutrient and non-nutrient components of fruits and vegetables. We have studied the prevention of skin tumor promotion by apigenin, a plant flavonoid. Apigenin may block several points in the process of tumor promotion, including inhibiting kinases, reducing transcription factors and regulating cell cycle. The complexity of our diets and the multitude of potential dietary effects which may be important in cancer development make this a fertile area for future study.
Anticarcinogenic Agents↗
Dietary energy restriction-induced modulation of protein kinase C zeta isozyme in the hamster pancreas.
Dietary restriction in experimental animals enhances life span, delays disease, inhibits immunological perturbations, and ameliorates cancer. Protein kinase C (PKC) isozymes mediate signals generated by hormones, growth factors, and neurotransmitters for cell proliferation and differentiation. The results of our study showed that a C-terminally directed anti-PKC zeta antibody detected an 81-kDa band in the pancreases of control and energy-restricted hamsters. Syrian golden hamsters were fed energy-restricted diets formulated such that the hamsters received 90% (10% energy restriction (ER)), 80% (20% ER), or 60% (40% ER) of the total energy consumed by control hamsters, with the energy reduced proportionally from fat and carbohydrate. ER decreased PKC zeta isozyme levels by 40-75% in hamsters fed 10, 20, and 40% ER diets for 8 wk. PKC zeta isozyme expression was decreased by 75-80% in hamsters fed ER diets for 15 wk. Although ER caused significant decreases in PKC zeta isozyme levels compared with those of control hamsters at both time points, the relative differences in PKC zeta levels between the dietary ER groups (10, 20, and 40%) were small and not significant. A significant decrease in the body weights of ER animals compared with those of controls was observed at both time points. No differences in tomato lectin and phytohemagglutinin reactivity were observed between control animals and animals fed 10, 20, and 40% ER diets. Furthermore, the cellular expression of PKC zeta in the hamster pancreas did not differ among hamsters fed the various ER diets. These observations may be important for understanding not only the role of dietary ER in pancreatic cancers but also PKC zeta signal transduction mechanisms in normal pancreatic physiology.
Animal Feed↗
Identification of protein kinase C zeta isozyme in hamster pancreas and pancreatic carcinoma cell lines.
Cellular differentiation and proliferation are dependent upon phosphorylation by endogenous protein kinase C (PKC) isozymes in many cell types. Western blotting with a C-terminally directed rabbit polyclonal anti-PKC zeta antibody detected a doublet of approximately 81 kDa in normal hamster pancreatic tissue and hamster pancreatic carcinoma (PC-1) and human pancreatic carcinoma (PANC-1) cells. Preabsorption of the antibody with the specific peptide blocked the appearance of the 81-kDa band, indicating that the band was specifically recognized by the PKC zeta antibody. In contrast, antibodies for PKC alpha, beta, gamma, delta, and epsilon failed to show specific immunoreactivity for normal pancreatic tissue or PANC-1 or PC-1 cells. Immunocytochemical analysis identified PKC zeta in the cytoplasm of ductules and large ducts, to a lesser extent in the islets of the hamster pancreas, and in the normal cultured pancreatic duct epithelial cells and pancreatic carcinoma (PANC-1 and PC-1) cell lines. Specific reactivity was seen by electron microscopy in the ductal cells of the normal pancreatic tissue. In normal pancreatic ductal tissue and primary pancreatic ductal hyperplasia and carcinoma, the proportional labeling of PKC zeta in nuclei and cytoplasm was similar. Our results demonstrating the presence of PKC zeta isozyme in the normal pancreas, cultured normal pancreatic duct epithelial cells, and pancreatic carcinoma cells or carcinoma tissue suggests a role for this isozyme in the normal physiology of the pancreas and perhaps in pancreatic carcinoma.
Amino Acid Sequence↗
Dietary modulation of epidermal protein kinase C: mediation by diacylglycerol.
Studies on the mechanism of dietary fat and energy modulation of skin carcinogenesis suggest that these diets may act through the cellular binding site of the phorbol ester tumor promoters, protein kinase C (PKC). High-fat diets increase the activity of PKC but have no impact on the steady-state protein levels. Energy restriction reduces the activity of PKC, presumably through reduction in the steady-state levels of particular isoenzymes (PKC alpha and PKC zeta). Phorbol-binding studies with epidermal cells from mice fed energy-restricted diets indicated a reduction of phorbol-binding sites in these cells. Investigations into lipid metabolism showed that both dietary fat and energy restriction increased epidermal cell diacylglycerol (DAG). The increase in DAG in cells from energy-restricted mice may be due to increased turnover of phosphatidylinositol, as was evident in the reduced phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-biphosphate and elevated inositol biphosphate and inositol triphosphate in these cells.
Animals↗
Effect of gastroduodenal juice and dietary fat on the development of Barrett's esophagus and esophageal neoplasia: an experimental rat model.
BACKGROUND: Reflux of duodenal content into the lower esophagus of rats enhances the formation of nitrosamine-induced esophageal cancer and results in the induction of adenocarcinoma. We investigated the extent of the mucosal injury that was produced when the lower esophagus of rats was exposed to the reflux of gastroduodenal juice in the presence or absence of a carcinogen and tested the hypothesis that induction of esophageal cancer in this model would be influenced by the intake of dietary fat. METHODS: Esophagoduodenostomy with gastric preservation was performed in 165 Sprague-Dawley rats in order to expose the lower esophagus to the reflux of gastroduodenal juice. Postoperatively selected groups of rats were treated with the carcinogen methyl-n-amylnitrosamine (MNAN). Subsequently, rats were fed diets of differing fat and calorie content for 20 weeks until they were put to death. RESULTS: Refluxed gastroduodenal juice, in the absence of MNAN, induced esophageal inflammatory changes (diffuse papillomatosis and hyperkeratosis) in 38 of 39 rats (97%), specialized columnar metaplasia (Barrett's esophagus) in four of 39 (10%), dysplasia in three of 39 (8%), and squamous cell carcinoma in one of 39 (3%). Diet did not influence the incidence of neoplasia in the absence of MNAN treatment. In rats treated with MNAN, refluxed gastroduodenal juice induced inflammation in 110 of 111 rats (99%), columnar metaplasia in 14 of 111 (13%), and cancer in 63 of 111 (57%). Fifty-eight percent of esophageal tumors were squamous cell carcinoma and 42% were adenocarcinoma. The highest incidence of tumors was observed in rats fed the semipurified high-fat diet (24 of 29; 83%) compared with rats fed the semipurified control diet (13 of 29; 45%), semipurified, calorie-restricted diet (15 of 27; 55%), and chow diet (11 of 26; 42%), p < 0.05. CONCLUSIONS: Reflux of gastroduodenal content into the lower esophagus of rats can induce both Barrett's metaplasia and neoplasia. Addition of a carcinogen increases the tumor yield and results in a proportion of the lesions being adenocarcinoma. This carcinogenic process is promoted by a diet with a high fat content.
Adenocarcinoma↗
Consumption of reduced-energy/low-fat diet or constant-energy/high-fat diet during mezerein treatment inhibited mouse skin tumor promotion.
Previous studies in our laboratory have shown that promotion of two-stage skin carcinogenesis in the SENCAR mouse model was inhibited in mice fed energy-restricted/low-fat diets, and elevated in mice fed high-fat diets. Studies reported here describe the influence of dietary energy restriction from fat and carbohydrate (ER) or high-fat (HF) diet on early promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) and on late promotion by mezerein (MEZ). Female SENCAR mice were initiated topically with 10 nmol 7,12-dimethylbenz[a]anthracene (DMBA) in 0.2 ml acetone at 9 weeks of age. For the following 2 weeks they received 3.2 nmol TPA in 0.2 ml acetone twice weekly, and for the next 16 weeks they received 10 nmol MEZ in 0.2 ml acetone twice weekly. All mice were fed control diet before TPA began and following the final MEZ treatment. Control mice received the control diet (c) throughout TPA and MEZ (C/C). The six experimental groups received: (1) ER diet throughout TPA and MEZ treatment (ER/ER); (2) HF diet throughout TPA and MEZ treatment (HF/HF); (3) ER during TPA (ER/C); (4) ER during MEZ (C/ER); (5) HF diet during TPA (HF/C); or (6) HF diet during MEZ (C/HF). Papilloma incidence and multiplicity, and carcinoma incidence were similarly reduced in the mice fed ER diet during MEZ (ER/ER and C/ER groups). In comparing the HF groups, papilloma multiplicity was highest in the HF/C group, intermediate in the C/C and lowest in the C/HF groups, but papilloma and carcinoma incidences were not modified by the HF diet protocols. Papilloma regression was greater in the C/HF group (27%, 4 regressions/15 tumor-bearing mice) than in the controls (0/18) during weeks 21-23, immediately following the end of MEZ treatment (P < 0.05).
9,10-Dimethyl-1,2-benzanthracene↗
Dietary energy restriction and fat modulation of protein kinase C isoenzymes and phorbol ester binding in Sencar mouse epidermis.
The purpose of our research is to understand the biochemical basis for dietary enhancement of phorbol ester induced tumor promotion in mice fed high-fat (HF) diet, and the inhibition of promotion in mice fed diets restricted in energy from fat and carbohydrate (ER). The present study assessed the presence of protein kinase C (PKC) isoenzymes in the Sencar mouse epidermis by Western blot and determined the influence of diet on the isoenzymes found. Mice were fed control, HF (24.5% corn oil) or ER (60% of control energy) diets for 6-29 weeks. Our initial studies assessed the immunoreactive levels of PKC alpha, beta, gamma, delta, epsilon and zeta and PKC alpha beta gamma using an antibody to a shared epitope. We detected PKC alpha, epsilon, delta and zeta in sufficient quantity for dietary studies. Dietary fat and energy did not significantly modify the presence of PKC epsilon or delta. We observed a 30% and 40% reduction in PKC alpha in comparison with control diet in cytosolic and particulate fractions respectively, from mice pre-fed ER diet. Reductions of 72% and 82% in cytosolic and particulate PKC were observed respectively with the alpha beta gamma antibody. ER diet reduced the overall amount of PKC zeta in cytosol and particulate by 42% and 59% respectively, with the cytosolic reduction being greater in mice pre-fed the restricted diets for 21-29 weeks. HF diet did not modify the protein levels of the PKC isoenzymes studied. The level of phorbol-12,13-dibutyrate binding to epidermal cells was assessed to determine if the reduction in PKC protein in the epidermis of ER mice would result in altered phorbol binding. Phorbol binding in cells isolated from mice fed ER diet was reduced in mice pre-fed the ER diet for 20-22 weeks in comparison with binding to cells from mice fed control diet. These results suggest that ER diet reduces specific PKC isoenzymes and the binding of phorbol esters in epidermis of mice. These observations may account for the inhibition of phorbol ester promotion of skin tumors in ER mice.
Animals↗
Increase in p53 protein half-life in mouse keratinocytes following UV-B irradiation.
Exposure of mammalian cells to UV radiation and other DNA-damaging agents triggers a response known as the UV response. This induction response involves a large number of genes including c-jun, cell-cycle regulatory proteins, specific repair enzymes, and the tumor suppressor gene p53. Altered expression of these genes following DNA damage is hypothesized to result in G1 arrest, thereby allowing cells to repair DNA damage prior to cell division. In the present study, we investigated expression of the p53 gene in mouse keratinocyte cell line 308 after exposure to UV-B light at a biologically relevant dose. Irradiation of 308 cells with 40 J/m2 UV-B resulted in a 4- to 10-fold induction in the level of p53 protein, peaking at 5 h post-irradiation. Northern blot analysis of RNA from UV-B irradiated cells showed no change in the steady-state level of p53 mRNA following irradiation. However, the half-life of p53 protein in UV-B irradiated 308 cells was extended approximately 7-fold, from 30 to 200 min. Additional studies were performed with specific anti-p53 monoclonal antibodies to establish whether UV-B irradiation induced a conformational change in p53 protein in irradiated cells. Metabolic labeling with 35S-methionine followed by immunoprecipitation with p53 monoclonal antibody PAb246, which recognizes the wild-type murine p53 protein, demonstrated that the p53 protein present in 308 cells possessed the wild-type conformation both before and after UV-B irradiation. In contrast, p53 antibody PAb240, which recognizes a 'conformation-dependent' epitope, was not reactive with the p53 protein present in 308 cells. Therefore, we conclude that the induction of p53 protein in mouse keratinocytes following UV-B irradiation occurred posttranscriptionally, and was due to a significant increase in p53 protein half-life.
Animals↗
Protein kinase C activity is reduced in epidermal cells from energy-restricted SENCAR mice.
Female SENCAR mice were pre-fed a control or 40% energy-restricted (ER) diet with energy removed from fat and carbohydrate, or a control, balanced high fat (BHF, with similar energy from fat and carbohydrate), 35% energy restricted from fat (HCR) or 35% energy restricted from carbohydrate (HFR) diet. Epidermal cells were isolated by trypsin digestion for measurement of protein kinase C (PKC) activity, lipid composition or lipid metabolism. Dietary restriction of fat or carbohydrate energy (HFR or HCR group) reduced particulate PKC activity in epidermal cells compared with cells from control mice. The ratio of soluble particulate PKC activity was higher in epidermal cells from mice fed the HCR diet compared with those fed the HFR diet. Diet did not affect soluble PKC activity. Inositol accumulation was measured in the water- or lipid-soluble fractions of prelabeled ([3H]inositol) epidermal cells following a 1-h incubation in media with LiCl. Phosphatidylinositol, inositol biphosphate and inositol triphosphate fractions were more heavily labeled in cells from mice fed the ER diet. Energy restriction did not modify epidermal total lipid or phospholipid composition, but 1,2-diacylglycerol levels were elevated in relation to cell number in epidermal cells from mice fed the ER diet. These data suggest that dietary energy restriction modified PKC activity through a pathway other than alteration in membrane lipid composition or inositol lipid metabolism.
Animals↗
Inhibition of skin tumor promotion by restriction of fat and carbohydrate calories in SENCAR mice.
The purpose of this research was to compare the influence of calorie restriction by removal of fat with calorie restriction by removal of carbohydrate on the promotion of skin tumorigenesis in mice. Female SENCAR mice were initiated with 7,12-dimethylbenz(a)anthracene (10 nmol, single topical treatment) and fed calorie-restricted diets during and following promotion with 12-O-tetradecanoylphorbol-13-acetate (2 micrograms, topically, twice a week for 20 weeks). Control diet (American Institute of Nutrition-based formulation) was compared with a diet in which calories from fat and calories from carbohydrate were similar [balanced high fat (BHF)] in ad libitum-fed groups. Restricted animals were fed diets such that 35% of the calories from fat [high carbohydrate, calories restricted from fat (HCR)] or from carbohydrate (high fat, calories restricted from carbohydrate) were restricted, but other intake was equivalent to the BHF group. Results showed an inhibition of papilloma number in both restricted groups and the inhibition was greatest in the HCR mice. Larger papillomas were observed on mice in the control, BHF, and high-fat, calories restricted from carbohydrate diet groups than on mice in the HCR group. The pattern of carcinoma development was similar in the mice in the freely fed control and BHF groups. Restriction of calories from either fat or carbohydrate delayed the rate and reduced the incidence of carcinoma development. Carcinoma incidence did not differ between mice fed the high-fat, calories restricted from carbohydrate and HCR diets.
9,10-Dimethyl-1,2-benzanthracene↗
Metabolism of carcinogenic nitrosamines in the rat and human esophagus and induction of esophageal adenocarcinoma in rats.
The mechanism is discussed by which certain nitrosamines induce esophageal papillomas and squamous cancer in rats, and some evidence is presented for the view that nitrosamines also induce the same cancer in humans, especially in China and South Africa. Studies on the metabolism of nitrosamines by cytochrome P450 isozymes in rat and human esophagus, including the activation reactions of formaldehyde and pentaldehyde formation from methyl-n-amylnitrosamine (MNAN), are reviewed. These reactions are catalyzed by microsomes from the rat and human esophagus, probably because these microsomes contain specific cytochrome P450 isozymes. Evidence is reviewed for the occurrence of nitrosamines related to MNAN in fungus-infected corn. The incidence of esophageal adenocarcinoma is rising in Western countries. The precursor lesion, Barrett's esophagus, is associated with colon cancer, suggesting a role for bile salts in the induction of the esophageal tumor. Studies are described in which rats were subjected to esophago-duodenostomy (joining the duodenum to the esophagus) and then treated with nitrosamines that normally induce esophageal squamous cancer. Adenocarcinomas of the lower esophagus were induced as well as Barrett's esophagus (under one set of conditions). Feeding a high-fat diet with this system increased the incidence of esophageal adenocarcinoma. This tumor was not induced when the operation was changed to esophago-gastroplasty (widening the lower esophageal sphincter). These results support a role of reflux of duodenal contents (including bile and pancreatic juice) rather than of gastric contents in the etiology of human esophageal adenocarcinoma.
Adenocarcinoma↗
Dietary energy and fat effects on tumor promotion.
We investigated dietary modulation, by energy level and energy source, of two-stage skin tumorigenesis initiated with 7,12-dimethylbenz(a)anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate in SENCAR mice. Studies comparing the influence of dietary calorie restriction (feeding less carbohydrate and less fat) with diet restriction and with ad libitum control feeding indicated an inhibition of papillomas and carcinomas in both restricted groups. The inhibition was greatest in the calorie-restricted group. We reported an increase in the number and incidence of papillomas and the earlier appearance of carcinomas in mice fed a high-fat diet during promotion, in comparison with control groups fed the same calorie allotment. Recent work compared restriction of fat calories (high carbohydrate, restricted fat) with restriction of carbohydrate calories (high fat, restricted carbohydrate), and both protocols resulted in fewer papillomas and carcinomas. Restriction of fat calories resulted in a greater inhibition of papillomas, whereas carcinoma rates were comparable with both protocols. Protein kinase C activity in epidermal cells from mice fed the high-fat diet was higher than activity from mice fed the control diet. Calorie restriction reduced protein kinase C activity. Phosphatidylinositol-inositol phosphate labeling studies suggest alteration of inositol lipid turnover in epidermal cells from mice fed a calorie-restricted diet.
9,10-Dimethyl-1,2-benzanthracene↗