The Triservice Anaesthetic Apparatus: a review.

The Triservice Anaesthetic Apparatus was designed around 30 years ago as a robust and highly portable anaesthesia delivery system for medical support to airborne operations and it has been the core anaesthesia system for the Defence Medical Services since then. Over this period there have been a number of equipment changes but issues remain which are in part mitigated by recent training developments. This article reviews these changes and developments and considers the future of this equipment.

Effect of dietary protein on N-nitrosobis(2-oxopropyl)amine-induced carcinogenesis and on spontaneous diseases in Syrian golden hamsters.

For assessment of the effect of dietary protein on spontaneous diseases and on the carcinogenicity of N-nitrosobis(2-oxopropyl)amine [(BOP) CAS: 60599-38-4], Syrian golden hamsters were fed either low protein (LP; 9% casein), medium protein (MP; 18% casein), or high protein (HP; 36% casein) in a diet containing a medium fat (corn oil) level. The experimental design permitted distinguishing between the effects of protein levels on initiation and development of various lesions in hamsters, in comparison with a control group that was given MP diet for life. When fed after BOP treatment, HP diet inhibited, among induced tumors, pulmonary adenomas in males. Among spontaneous diseases, LP diet fed before 8 weeks of age enhanced colitis in both males and females, renal and adrenal gland amyloidosis in males, and gastric vascular calcinosis in males but inhibited liver abscesses and liver cysts in both males and females. When fed after 8 weeks of age, LP diet enhanced gastric and renal vascular calcification and parathyroid gland adenomas in both sexes but inhibited hepatic, renal, and adrenal gland amyloidosis in females and liver abscesses and liver cysts in both males and females. The feeding of HP diet before 8 weeks of age enhanced the development of colitis and adrenal gland lipomatosis in both males and females but inhibited the development of adrenal gland amyloidosis and adrenal cortical cell hyperplasia in males. When fed to hamsters after 8 weeks of age, HP diet increased the incidence of adrenal gland amyloidosis in females and colitis in both males and females but reduced the frequency of liver cysts in both males and females and of adrenal cortical cell hyperplasia in males. The overall data and literature review indicate that the effect of dietary protein on tumorigenesis is tissue, sex, species, and strain related.

Interaction of dietary fat and protein in spontaneous diseases of Syrian golden hamsters.

The influence of interactions between dietary fat and protein on spontaneous diseases was investigated in Syrian golden hamsters fed two levels of corn oil [4.5 or 18 g/385 kilocalories (kcal)] with each of two levels of casein (9 or 36 g/385 kcal). The four diets were fed to separate groups in two different sequences: 1) Diets were given during weeks 3-7 and followed by control diet (9 g corn oil and 18 g casein/385 kcal), or 2) control diet was fed during weeks 3-7, and the four diets were fed from week 8 until death. Dietary interactions of fat and protein modified spontaneous degenerative, inflammatory, and proliferative diseases in hamsters. For example, amyloidosis in the liver, kidneys, spleen, and adrenal glands was reduced in females by feeding high-fat-high-protein (HF-HP) diet in comparison with low-fat-high-protein (LF-HP) diet during weeks 3-7 or by feeding LP diets at either fat level after 8 weeks. The incidence of hepatic abscess was highest in males consuming HP diet at either fat level after 8 weeks, and hepatic necrosis was observed most often in hamsters fed HF-HP diet after 8 weeks. Gastric and renal vascular calcification and nephrocalcinosis incidences were reduced by 50-100% in hamsters fed HF-HP diet after 8 weeks, and HF diet fed at this time reduced vascular calcification in the heart in both sexes and in the lungs in males. Inflammation was generally influenced similarly by diets fed either during weeks 3-7 or after 8 weeks. In the prostate gland, inflammation was observed most frequently in males fed HF-LP diet; however, in the vagina inflammation was elevated in females fed HF-HP diet and found in the gallbladder more commonly in hamsters fed HF-HP than in those given LF-HP. The incidence of colitis was decreased by giving HF-LP diet during weeks 3-7 or LF-LP diets after week 8. The incidence of gastric ulcer was high in males fed HF diets during weeks 3-7, and intestinal ulcers were high in those fed LF-LP at this time. The adrenal hyperplasia incidence was highest in males given HF-HP diet before or after 8 weeks and in females given this diet after 8 weeks. Similarly, ovarian and hepatic ductal hyperplasia was highest in females fed HF-HP diet after 8 weeks, and gastric and intestinal hyperplasia increased with the rise in fat at both protein levels in both sexes.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of the interaction of dietary fat and protein on N-nitrosobis(2-oxopropyl)amine-induced carcinogenesis and spontaneous lesions in Syrian golden hamsters.

Syrian golden hamsters were fed four diets in experiments designed to evaluate the effects of the interaction of dietary fat and protein on carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine [(BOP) CAS: 60599-38-4]. The diets consisted of two levels of dietary fat [4.5 g (low fat, LF) or 18 g (high fat, HF) of corn oil/385 kilocalories (kcal)]. These levels were fed with each of two levels of dietary protein [9 g low-protein (LP) and 36 g high-protein (HP) casein/385 kcal]. The four diets were fed to two separate groups of hamsters at two different periods in their life-span. For testing of the effects of diet on tumor initiation, one group received the diets from 3 to 7 weeks of age. At 8 weeks, they were given injections sc of 10 mg BOP/kg body weight and placed on a control diet [9 g corn oil (medium fat) and 18 g casein (medium protein)/385 kcal]. The other group received control diet until 8 weeks of age, at which time they were given injections of BOP and placed on the four diets. This group was designed to test the effects of the diets on tumor development. BOP-induced lesions in the lungs, liver, common bile duct, gallbladder, and kidneys are described; results in the pancreas were reported separately. In hamsters fed the four diets after BOP treatment, the LF-LP groups had the fewest tumors, the LF-HP-fed and HF-LP-fed groups had intermediate yields of tumors, and the hamsters given HF-HP diet exhibited the largest numbers of neoplasms. Several specific tumor types showed a similar pattern. For example, the pulmonary adenoma incidence, which was low in the non-BOP-treated hamsters, was higher in the HF-HP group than in those fed LF-HP diet after BOP, but it was not influenced by fat at the LP level. In addition, renal adenomas were observed at a low incidence in non-BOP-treated hamsters and in hamsters fed LF-LP levels before or after BOP treatment (0.5% incidence) but were present at an 8% incidence in all other BOP-treated groups. The incidence of biliary cystic adenomas was highest in male hamsters that received HF diets, irrespective of BOP treatment, and BOP treatment resulted in increased yields of this lesion in females only in groups given HF-LP diet.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased tumorigenesis induced by N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters fed high-fat diets.

The effects of dietary fat on carcinogenesis were presented, with the pancreas excluded, in randombred Syrian golden hamsters after administration of N-nitrosobis(2-oxopropyl)amine (BOP). Diets containing 4.5, 9, or 18 g corn oil/385 kilocalories [low-fat (LF), medium-fat (MF), or high-fat (HF) diet, respectively] were fed in two sequences. In the first sequence during which the effects of fat on the initiation phase of BOP carcinogenicity were examined, LF or HF diets were fed to hamsters 3-7 weeks of age and for 2 days after a single sc BOP treatment (10 mg/kg body wt) to 8-week-old hamsters. These hamsters were then given MF diet for the remainder of their lives. In the second sequence during which the role of fat on the promotional phase (development) of BOP-induced cancer was evaluated, MF diet was fed during the weeks preceding BOP treatment and LF or HF levels were given after BOP treatment. Separate groups were fed MF diet throughout both phases, and parallel animal groups received each diet sequence and were treated with saline at 8 weeks of age. Renal adenocarcinomas in males were observed only in those given HF diet either before or after BOP treatment (9% incidence). Similarly, pulmonary adenoma and intraphepatic biliary cystic adenoma (cholangioma) incidences were elevated above spontaneous rates in HF-fed groups. This study demonstrated that dietary fat enhanced BOP-induced tumorigenesis in the kidneys, lungs, and liver when fed, either during initiation (preceding carcinogen treatment) or at promotional stages (following carcinogen treatment).

Modifying factors in pancreatic carcinogenesis in the hamster model. IV. Effects of dietary protein.

The possible effects of dietary protein on pancreatic cancer induced in outbred Syrian golden hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) were studied. Three levels of casein as protein at low [LP = 9 g/385 kilocalories (kcal)], medium (MP = 18 g/385 kcal), or high levels (HP = 36 g/385 kcal) were fed in two sequences to 4 groups of hamsters. The effects of protein level on the initiation phase of BOP carcinogenesis were examined in hamsters fed LP or HP from 3 through 7 weeks of age, followed by MP for the remainder of their lives. The role of protein level on the promotional (developmental) phase of carcinogenesis was evaluated in hamsters fed (from 3 through 7 wk of age) MP, followed by LP or HP for the rest of their lives. One-half of the hamsters from each of the 4 groups received a single sc BOP injection (10 mg/kg body wt) at 8 weeks of age. Changes in diet from one type to the other occurred 2 days after BOP treatment. An MP diet fed before and after BOP served as the experimental control diet. The results demonstrated that the LP diet inhibited the developmental phase of carcinogenesis only in females, whereas the MP and HP diets did not affect initiation or promotion of cancer in either sex. The inhibitory effect of the LP diet in pancreatic carcinogenicity only in females calls for further studies.

Influence of dietary fat on spontaneous lesions of Syrian golden hamsters.

Dietary corn oil was consumed by Syrian golden hamsters at levels of 4.5 g [low fat (LF)] or 18 g [high fat (HF)]/385 kilocalories (kcal) from 3 to 7 weeks of age followed by a diet containing 9 g [medium fat (MF)]/385 kcal for life. In other groups MF diet was given from 3 to 7 weeks of age and followed by either LF or HF for life. A separate group was fed MF continuously after 3 weeks of age. Spontaneous lesions, which were altered by these dietary protocols, are reported. An HF diet fed after 8 weeks increased the incidence of flank organ hyperplasia and prostatitis, but it decreased prostatic fibrosis in males. Consumption of HF diets after 8 weeks by females increased survival and resulted in an elevated incidence of thyroid adenomas, ovarian cell hyperplasia, vaginal papillomas, and adrenal cortical cell adenomas. In age-adjusted data the increase in ovarian cell hyperplasia and adrenal cortical cell adenomas was shown to be due to HF diet and not to be a consequence of extended survival. Periodontitis and calcification of cardiac tissues decreased in hamsters fed HF diets after 8 weeks, but cell vacuolization and hyperplasia of the anterior pituitary gland and epithelial hyperplasia in the forestomach were increased. Salivary gland adenocarcinomas were observed only in hamsters fed HF diets. Feeding HF levels, either during weeks 3-7 or after week 8, decreased osteofibrosis and otitis media and increased urinary bladder epithelial hyperplasia, adrenal cortical cell lipomatosis, and bone chondrosis. Calcification of gastric and renal arteries decreased as dietary fat levels increased either before or after 8 weeks of age in males and only when fed after 8 weeks in females. Colitis and focal glandular hyperplasia of the colon mucosa were increased in both sexes by an HF diet being given before or after 8 weeks of age.

Enhancement of experimental pancreatic cancer in Syrian golden hamsters by dietary fat.

The effects of dietary fat on the induction and development of pancreatic ductular adenocarcinoma were studied in randombred Syrian golden hamsters. Diets containing low-fat (LF) or high-fat (HF) levels of corn oil [4.5 or 18.0 g/385 kilocalorie (kcal)], contributing 10 or 41% of the calories, respectively, were fed either before or after a single injection of N-nitrosobis(2-oxopropyl)amine (BOP) (10 mg/kg body wt). Control hamsters were fed corn oil at a medium-fat (MD) level (9 g/385 kcal) for life. The incidence of ductular adenocarcinomas increased in both males and females (LF diet, 16%; HF diet, 34%) when the HF diet was fed after BOP treatment. The average number of carcinomas per carcinoma-bearing animal also increased (LF diet, 1.3; HF diet, 3.0), but the carcinoma incidence was not influenced by these diets being fed before carcinogen treatment. The incidence of ductular adenomas was high with all treatments and was not influenced by diet. However, the number of adenomas was increased in animals fed HF diets. In addition, the incidence of acinar cell nodules was elevated in animals fed the MF and HF diets after BOP administration. These results showed that dietary fat modified the development of experimental ductular adenocarcinoma of the pancreas.

Interaction of dietary fat and protein on pancreatic carcinogenesis in Syrian golden hamsters.

The role of interactions between dietary fat and protein in experimental pancreatic cancer was determined in Syrian golden hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Two levels of corn oil [4.5 and 18 g/385 kilocalorie (kcal)] were fed with each of two levels of casein (9 g/385 kcal and 36 g/385 kcal), either before or after a single sc injection of BOP (10 mg/kg body wt) at 8 weeks of age. Control diet was fed at other times (9 g corn oil and 18 g casein/385 kcal). The pancreatic ductular carcinoma incidence and multiplicity (average No. of tumors/tumor-bearing animals) increased as dietary fat and protein levels rose in hamsters fed the four diets after carcinogen treatment. Enhanced carcinogenesis by high-fat (HF) diets occurred only in hamsters fed the high-protein (HP) level, and protein effects were seen only with the HF diets. The low-fat-low-protein (LF-LP) diet inhibited pancreatic carcinogenesis among the hamsters given the four diets before BOP treatment. Pancreatic adenoma yields were elevated in hamsters given either HF or HP diets following BOP treatment, by comparison with the low levels. However, when diets were fed before BOP treatment, an increased yield occurred with the rise in protein, but the yield was reduced in males with the increase in fat. Acinar cell nodules were observed primarily in hamsters fed LP levels after BOP, and their multiplicity was highest in those given the HF diet. The interaction between dietary fat and protein demonstrated the interdependence of the effects of these two nutrients on pancreatic carcinogenesis in hamsters.

Effects of dietary selenium on bis(2-oxopropyl)nitrosamine-induced carcinogenesis in Syrian golden hamsters.

In studies designed to determine the influence of dietary Se on pancreatic carcinogenesis, Syrian golden hamsters were fed unsupplemented torula yeast diet or diet supplemented with 0.1 or 5.0 ppm Se, from sodium selenite, starting at 4 weeks of age until the termination of the study. In separate groups, hamsters were given the diet supplemented with 0.1 ppm Se until 5 days after carcinogen treatment. Then they were fed either the unsupplemented diet or the diet supplemented with 5.0 ppm Se until the end of the experiment. N-Nitrosobis(2-oxopropyl)amine (BOP; CAS; 60599-38-4) treatment was given as a single sc injection of 20 mg/kg (body wt) at 8 weeks of age, and surviving hamsters were killed 50 weeks later. As a measure of Se status, glutathione peroxidase (GSHPX) activities were determined in plasma, erythrocytes, and liver. Values were elevated in animals fed higher levels of dietary Se. BOP treatment depressed plasma GSHPX at 24 hours and elevated erythrocyte and liver values at 4 weeks. Pancreatic ductular adenoma yields were inhibited with each elevation of dietary Se in female hamsters fed the diets, both before and after BOP administration, and were further inhibited in females that were fed diets containing 0.1 ppm Se before BOP administration and that were changed to the unsupplemented or 5.0-ppm-supplemented diets after BOP was given. Pancreatic ductular adenoma yields were highest in all male groups given diets of 0.1 ppm Se before BOP administration, irrespective of the Se level after BOP was fed. Adenoma yields in males were lowest in hamsters fed unsupplemented diet, both before and after BOP treatment. Pancreatic carcinoma yields were low and not influenced by dietary Se. The incidence of hepatic necrosis was elevated in BOP-treated hamsters fed the unsupplemented diet, and that of biliary cystic adenomas was highest in the group fed 0.1 ppm Se before and after BOP treatment.

Modifying factors in pancreatic carcinogenesis in the hamster model. I. Effect of protein-free diet fed during the early stages of carcinogenesis.

The role of protein in pancreatic carcinogenesis was examined in outbred Syrian golden hamsters treated with the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) and fed a purified protein-free diet (PPFD). The PPFD was fed for 28 days from 8 weeks of age; before and after animals were fed PPFD, they were given a commercial diet (CD). BOP was given before PPFD feeding (group 1) or at 18 days (group 2) and 28 days (group 3) from the beginning of the PPFD feeding. BOP-treated control hamsters (group 4) were pair-fed a purified control diet (PCD) instead of PPFD. All animals fed PPFD and PCD were returned to a CD for the rest of the experiment, which was terminated in each group 52 weeks after BOP treatment. The results showed a highly significant reduction of tumor incidence (P less than 0.0001) in hamsters that received PPFD, when compared to those fed PCD, regardless of the time of carcinogen administration during the dietary regimen. Hamsters treated with BOP at 18 days of PPFD (group 2) developed neither benign nor malignant pancreatic tumors. The inhibition of pancreatic neoplasms was not related to reduced calorie consumption, since this occurred in the BOP-treated hamsters that were pair-fed the PCD diet. The results indicated that both the initiation and promotion of pancreatic carcinogenesis with BOP in hamsters can be inhibited by lack of protein in the diet given for 4 weeks during the early stages of the neoplastic process.

Inhibitory effect of apigenin, a plant flavonoid, on epidermal ornithine decarboxylase and skin tumor promotion in mice.

This investigation studied the effect of topical application of apigenin on skin tumorigenesis initiated by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA) in SENCAR mice. Apigenin was a potent inhibitor of epidermal ornithine decarboxylase induction by TPA in a dose-dependent manner from 1 to 20 mumol. Two tumorigenesis studies were conducted. In the first study, 20 mumol of apigenin was applied topically and no effect on body weight was observed. By week 33 after DMBA initiation, 48% of DMBA/TPA-treated mice developed carcinomas, while none occurred in DMBA/apigenin/TPA-treated groups. In the second study, doses of 5 and 20 mumol of apigenin were used. The papilloma incidence for 0, 5, and 20 mumol apigenin at 26 weeks after DMBA was 93.3, 58, and 39.3%, and papilloma numbers per mouse were 7.5, 2.5, and 1.8, respectively. Apigenin prolonged by 3 weeks the latency period of tumor appearance. In addition, apigenin significantly inhibited the incidence of carcinoma and the numbers of carcinomas. The incidence of carcinomas per tumor-bearing animal and the ratio of carcinomas/papillomas in two apigenin-treated groups decreased although there were no significant differences between the three groups. These data indicate that apigenin inhibited skin papillomas and showed the tendency to decrease conversion of papillomas to carcinomas.

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.

Dietary fat effects on the initiation and promotion of two-stage skin tumorigenesis in the SENCAR mouse.

We investigated the influence of dietary corn oil on initiation of skin tumors in SENCAR mice with 7,12-dimethylbenz(a)anthracene (DMBA) (10 nmol at 8 to 9 wk of age) and the promotion of these tumors with 12-O-tetradecanoylphorbol-13-acetate (TPA) (3.2 nmol twice weekly for 20 wk). Diet high in corn oil (24.6%) was fed, in comparison with control diet (5%), to mice during two time schedules: (a) high-fat diet was fed preceding and for 1 wk following DMBA to assess the effects of high corn oil diet on initiation; and (b) high-fat diet was fed starting at the time of the first TPA treatment (1 wk following DMBA initiation) until the end of the experiment to assess effects of high corn oil diet on promotion. Mice were trained to consume equivalent caloric allotments of the low- and high-fat diets to ensure that the observed effects on tumor development were for dietary fat at constant calorie intake. Feeding high corn oil diet during DMBA treatment did not influence the incidence of skin papilloma or carcinoma, but the number of papillomas per effective mouse was reduced in mice fed the high-fat diet during initiation. Consumption of the high corn oil diet during and following TPA treatment resulted in an increase in the incidence of papillomas up until Wk 14 of the experiment, an increase in the number of papillomas per effective mouse throughout the experiment, and an increase in the number of carcinomas per effective mouse during Wk 25 to 34. However, cumulative carcinoma yield (Wk 25-44) did not differ between the diet groups. Dietary treatment did not influence food consumption, body weight, or survival in the mice treated with DMBA and TPA. Northern blot hybridization studies were carried out on RNA purified from tumors of high- and low-fat mice to determine if diet influenced the pattern of Ha-ras oncogene expression. The results of this experiment indicated that elevated levels of Ha-ras-specific RNA, in comparison with normal epidermal RNA, were present in papillomas and carcinomas from DMBA-initiated, TPA-promoted mice irrespective of the diet the mice were fed.

Enhancement of pancreatic carcinogenesis in hamsters fed a high-fat diet ad libitum and at a controlled calorie intake.

An enhancement of pancreatic cancer induced by N-nitrosobis-(2-oxopropyl)amine (BOP) was reported previously in Syrian hamsters fed high-fat diet following carcinogen treatment. The purpose of our research was to determine if this enhancement was due to the consumption of more calories by the hamsters fed the high-fat diet. Male hamsters were treated with a single injection of BOP (20 mg/kg body weight s.c.) at 8 weeks of age. One week later they started either on a low-fat diet (4.3% corn oil) or a high-fat diet (20.5% corn oil) that was fed until the end of the experiment at 92 weeks after BOP. Diets were fed either ad libitum or in a control-fed protocol. The control-fed groups had equivalent calorie intakes and were restricted slightly in comparison with the ad libitum-fed hamsters. BOP treatment reduced survival slightly but survival did not differ significantly in accordance with dietary assignment. Body weight was elevated in the hamsters fed high-fat diet ad libitum in comparison with those fed low-fat diet ad libitum. However, differences were not observed in hamsters fed low- and high-fat diets by the control-fed protocol. Pancreatic carcinogenesis was enhanced about 3- to 4-fold when hamsters were fed high-fat diet by either protocol. The degree of enhancement did not differ with the feeding regimen. However, the higher death rate with pancreatic cancer occurred earlier in the ad libitum-fed hamsters than in the control-fed hamsters.

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.

Effect of L-tryptophan excess and vitamin B6 deficiency on rat urinary bladder cancer promotion.

To further evaluate the role of tryptophan and vitamin B6 in bladder carcinogenesis, male Fischer 344 rats were fed 0.2% N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) in semipurified diet or were given semipurified diet alone for 4 weeks. One week later, rats from each group were assigned for the remainder of the experiment to one of four experimental diets, labeled as follows: group 1, control semipurified; group 2, L-tryptophan excess (2%); group 3, vitamin B6-deficient (1.0 mg/kg diet); or group 4, L-tryptophan excess, plus vitamin B6-deficient diet. All surviving rats were killed at 80 weeks of the experiment. Throughout the study, body weights were reduced in the groups fed FANFT and, at 70 and 80 weeks, body weights were reduced in the groups given tryptophan excess. The incidence of urinary bladder carcinoma was highest in the group treated with FANFT, followed by diet with control tryptophan and vitamin B6 levels (40%). The disease incidence was reduced in the vitamin B6-deficient group (13%) and of an intermediate range in the groups fed a tryptophan excess with or without vitamin B6 deficiency (28-29%). Tumors at other sites were greatest in number in FANFT-treated rats fed vitamin B6-deficient diet with excess tryptophan and were significantly fewer in FANFT-treated rats fed vitamin B6-deficient diet alone. Animals given diet deficient in vitamin B6 consistently had depressed levels of alanine aminotransferase activity and plasma pyridoxyl phosphate. FANFT pretreatment decreased alanine aminotransferase activities in rats in some groups and the feeding of tryptophan had variable effects on alanine aminotransferase and plasma pyridoxyl phosphate levels. Urinary tryptophan metabolites were influenced by all treatments, but the results did not correlate with tumor yields. Urinary bladder ornithine decarboxylase activity was not altered in vitamin B6-deficient female rats. These results do not support the hypothesis that increased dietary L-tryptophan promotes bladder carcinogenesis in rats, but other dietary factors might modify the process following FANFT initiation.

Influence of diet and calorie restriction on the initiation and promotion of skin carcinogenesis in the SENCAR mouse model.

Diets were restricted to 60% of the intake of the control mice by feeding less diet (total diet restriction, TDR) or by feeding fewer calories from fat and carbohydrate (calorie restriction, CR) during the initiation or promotion phases of skin tumorigenesis in female SENCAR mice. Skin cancer was initiated by topical treatment with 10 nmol of 7,12-dimethylbenzanthracene in acetone and promoted by twice weekly treatments with 12-O-tetradecanoylphorbol-13-acetate in acetone for 20 wk. Dietary restriction preceding and during 7,12-dimethylbenzanthracene treatment did not influence skin papilloma or carcinoma yield. Papilloma incidence and the number of papillomas per effective mouse were reduced in mice restricted by both TDR and CR protocols during and following promotion with 12-O-tetradecanoylphorbol-13-acetate. Papilloma size was reduced at experimental wk 16 and 20 in both TDR and CR groups fed these diet regimens during promotion. However, by wk 28 and 32, papilloma sizes were similar in the control and TDR groups, and smaller papillomas were observed only in the CR group. The average carcinoma latency was extended by 26% in the groups restricted during promotion, and incidence was reduced in both groups. The reduction, however, was statistically significant only in the CR group. Body weight gain was reduced during the times when dietary restriction was enforced, and in a short-term study, both restricted diet treatments reduced the percentage of carcass protein.

Dietary agents in cancer prevention: flavonoids and isoflavonoids.

Flavones and isoflavones may play a prominent role in cancer prevention since these compounds are found in numerous plants that are associated with reduced cancer rates. This article reviews recent epidemiological and animal data on isoflavones and flavones and their role in cancer prevention. It covers aspects of the bioavailability of these dietary constituents and explores their mechanism of action. Human epidemiology data comes primarily from studies in which foods rich in isoflavones or flavones are associated with cancer rates. This approach has been particularly useful with isoflavones because of their abundance in specific foods, including soy foods. The bioavailability of flavones and isoflavones has been shown to be influenced by their chemical form in foods (generally glycoside conjugates), their hydrophobicity, susceptibility to degradation, the microbial flora of the consumer, and the food matrix. Some information is available on how these factors influence isoflavone bioavailability, but the information on flavones is more limited. Many mechanisms of action have been identified for isoflavone/flavone prevention of cancer, including estrogenic/antiestrogenic activity, antiproliferation, induction of cell-cycle arrest and apoptosis, prevention of oxidation, induction of detoxification enzymes, regulation of the host immune system, and changes in cellular signaling. It is expected that some combination of these mechanisms will be found to be responsible for cancer prevention by these compounds. Compelling data suggest that flavones and isoflavones contribute to cancer prevention; however, further investigations will be required to clarify the nature of the impact and interactions between these bioactive constituents and other dietary components.

Methodologic issues, theoretical considerations, and design criteria for experimental animal and cell culture experiments.

This article provides background information that is important when evaluating the relevance to humans of particular animal or in vitro experiments designed to assess the relations between fatty acids and cancer. Considerations in designing carcinogenesis studies to assess the relation between dietary fatty acids and human cancer include selection of the animal model and design of the experimental diets. Animal carcinogenesis models are generally best for evaluating the early phases of cancer development: the initiation and promotion of cancer. Transplantation protocols have been developed for evaluating the effect of diet on the growth and metastasis of partially or fully transformed cells. The variables that are important in such models are the origin and biology of the cell line, the animal host used for the implantation, the site of transplantation, whether the primary tumor is excised after a period of time to allow for metastasis, and when the diets are fed relative to the different phases of tumor growth and metastasis. Studies in cultured cells have been particularly useful for assessing the mechanisms by which fatty acids affect cancer. Considerations in designing studies with cultured cells include selection of the cell line, cell culture conditions, selection of biological endpoints that are relevant to human cancer, and in vivo confirmation of the mechanisms observed in vitro. Design considerations for each of these experimental approaches are discussed and the contributions of each approach are summarized.