Chemoprevention of head and neck cancer

The role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of exocrine and endocrine pancreas was investigated in conscious sheep. Intravenous infusions of PACAP-27 and PACAP-38 (1, 3, and 10 pmol/kg/min) for 10 min during phase II of the duodenal migrating myoelectric complex accelerated pancreatic protein and amylase outputs dose-dependently. The responses in enzyme secretion to both PACAPs at the highest doses were inhibited significantly by atropine infusion (14.4 nmol/kg/min). Vasoactive intestinal polypeptide (VIP) at 3 pmol/kg/min significantly accelerated protein but not amylase outputs, although the response to the highest dose was not significantly influenced by atropine. PACAP-27 and VIP increased pancreatic juice flow and bicarbonate output dose-dependently; however, the responses to the highest dose were not altered significantly by atropine. On the other hand, intravenous injection of PACAP-38 (100 pmol/kg) did not influence basal plasma concentration of insulin, glucagon, and glucose. Moreover, PACAP-38 (1-100 pmol/kg) altered neither pancreatic endocrine response to intravenous infusion of glucose (20 mumol/kg/min) not that to n-butyric acid (33 mumol/kg/min). These results suggest that PACAP contributes to the regulation of exocrine secretion of the ovine pancreas but not to endocrine secretion. PACAP appears to accelerate pancreatic enzyme secretion mostly via the cholinergic nerves.     

Inhibition of human cytochrome P450-catalyzed oxidations of xenobiotics and procarcinogens by synthetic organoselenium compounds

The effects of synthetic chemopreventive organoselenium compounds 1,2-, 1,3-, and 1,4-phenylenebis(methylene)selenocyanate (o-, m-, and p-XSC, respectively), benzyl selenocyanate (BSC), and dibenzyl diselenide (DDS) and inorganic sodium selenite on the oxidation of xenobiotics and procarcinogens by human cytochrome P450 (P450 or CYP) enzymes were determined in vitro. Spectral studies showed that BSC and three XSC compounds (but not sodium selenite or DDS) induced type II difference spectrum when added to the suspension of liver microsomes isolated from beta-naphthoflavone-treated rats, with m-XSC being the most potent in inducing spectral interactions with P450 enzymes; m-XSC also produced a type II spectral change with human liver microsomes. o-, m-, and p-XSC inhibited 7-ethoxyresorufin O-deethylation catalyzed by human liver microsomes when added at concentrations below 1 microM levels, but BSC and DDS were less effective. All of these compounds inhibited the oxidation of model substrates for human P450s to varying extents. We studied the effects of these compounds on the activation of procarcinogens by recombinant human CYP1A1, 1A2, and 1B1 enzymes using Salmonella typhimurium NM2009 tester strain for the detection of DNA damage. The three XSCs were found to be very potent inhibitors of metabolic activation of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, and 2-aminoanthracene, catalyzed by CYP1A1, 1A2, and 1B1, respectively. The potency of inhibition of m-XSC on CYP1B1-dependent activation of 2-aminoanthracene was compatible to those of alpha-naphthoflavone. These inhibitory actions may, in part, account for the mechanisms responsible for cancer prevention by organoselenium compounds in laboratory animals.     

Chemoprevention of azoxymethane-induced rat colon carcinogenesis by a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate

In our studies to find natural compounds with chemopreventive efficacy in foods, using azoxymethane (AOM)-induced colonic aberrant crypt foci and colonic mucosal cell proliferation as biomarkers, a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate (ACA), present in the edible plant Languas galanga from Thailand was found to be effective. This study was conducted to test the ability of ACA to inhibit AOM-induced colon tumorigenesis when it was fed to rats during the initiation or post-initiation phase. Male F344 rats were given three weekly s.c. injections of AOM (15 mg/kg body weight) to induce colonic neoplasms. They were fed diet containing 100 or 500 ppm ACA for 4 weeks, starting one week before the first dosing of AOM (the initiation feeding). The other groups were fed the ACA diet for 34 weeks, starting one week after the last AOM injection (the post-initiation feeding). At the termination of the study (week 38), AOM had induced 71% incidence of colonic adenocarcinoma (12/17 rats). The initiation feeding with ACA caused significant reduction in the incidence of colon carcinoma (54% inhibition by 100 ppm ACA feeding and 77% inhibition by 500 ppm ACA feeding, P = 0.03 and P = 0.001, respectively). The post-initiation feeding with ACA also suppressed the incidence of colonic carcinoma (45% inhibition by 100 ppm ACA feeding and 93% inhibition by 500 ppm ACA feeding, P = 0.06 and P = 0.00003, respectively). Such inhibition was dose-dependent and was associated with suppression of proliferation biomarkers, such as ornithine decarboxylase activity in the colonic mucosa, and blood and colonic mucosal polyamine contents. ACA also elevated the activities of phase II enzymes, glutathione S-transferase (GST) and quinone reductase (QR), in the liver and colon. These results indicate that ACA could inhibit the development of AOM-induced colon tumorigenesis through its suppression of cell proliferation in the colonic mucosa and its induction of GST and QR. The results confirm our previous finding that ACA feeding effectively suppressed the development of colonic aberrant crypt foci. These findings suggest possible chemopreventive ability of ACA against colon tumorigenesis.     

Plasma lipids, ketone bodies, and glucose concentrations in calves fed high- and low-fat milk replacers

Twenty-four 5-day-old male calves were fed twice daily milk replacers containing either 5% (low-fat) or 25% (high-fat) lard. Plasma lipids, blood glucose, and ketone bodies were determined in jugular blood before feeding and every hour during 8 h after feeding. The high-fat diet caused in the 1st h after feeding a sharp increase of triglycerides and phospholipids followed by a sharp decrease; these two increased slowly during the following 5 h. Within the first 2 h after feeding, there was an increase of cholesterol esters, free cholesterol, and nonesterified fatty acids. With the low-fat diet, triglycerides and cholesterol esters showed a small increase during the 4 h following meal whereas phospholipids, free cholesterol, and nonesterified fatty acids were not affected significantly. With both diets, blood glucose reached a maximum of 110 mg/100ml 1 h after feeding; ketone bodies were not altered significantly. With the high-fat diet, lipid digestion would occur in two phases; firstly, part of the fat would be lipolyzed quickly by pregastric esterase before clot formation in the abomasum; secondly, the rest of the lipids, slowly released by progressive lysis of the coagulum would be digested under the action of gastric and pancreatic lipases. The first phase did not occur with the low-fat diet.     

The role of apoptosis in the modulation of colon carcinogenesis by dietary fat and by the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate

Studies in laboratory animals have demonstrated that dietary supplements of organoselenium, 1,4-phenylenebis(methylene)selenocyanate (p-XSC) inhibit colon carcinogenesis. Diverse chemopreventive agents and clinically used anticancer drugs have been shown to induce apoptosis in colonic tumors. Inducing apoptosis is a key mechanism for the effectiveness of some chemopreventive agents; however, failure of apoptosis is now believed to contribute to the development of human cancer. In this study, we determined the number of apoptotic bodies in the colon tumors of rats fed a low-fat (LF) or a high-fat (HF) diet with or without p-XSC treatment. At 5 weeks of age, male F344 rats were divided into four groups, which were then maintained on one of the following diets: LF, 5% corn oil; HF, 23.5% corn oil; and LF and HF supplemented with 20 ppm p-XSC. In addition, the LF or HF diet with p-XSC supplements was administered either during the initiation stage or postinitiation. At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given 15 mg/kg of body weight of azoxymethane once weekly for 2 weeks. The animals were sacrificed 38 weeks after carcinogen treatment, and their colonic tumors were examined for appearance of apoptosis. The LF diet significantly increased the percentage of apoptosis as compared to the HF diet; the percentage of apoptosis in LF and HF diets were 12.4 and 2.9. The colon tumors that were present in the groups fed p-XSC together with a LF or a HF diet after carcinogen administration (postinitiation period) had a higher number of apoptotic bodies than those that were present in the animals fed p-XSC before carcinogen treatment (initiation period). The extent of apoptosis was weak when p-XSC was given with a HF diet (4.4%) during the initiation phase, but it was high significant when p-XSC was administered with LF diet (25.2%). Taken together, our data suggest that administration of LF diet supplemented with p-XSC increases apoptosis as compared to a HF diet alone.     

Growth and development of the kidneys, heart and liver in S 5B/P1 and Osborne-Mendel rats fed high or low-fat diets

Male Osborne-Mendel (OM) and S 5B/P1 rats were overfed from birth to 24 or 105 days. The effects of feeding a diet with 44 per cent or 3 per cent (w/w) fat, supplementary feeding during the suckling period, and reduced litter size, on body weight and on the weight and cellularity of the heart, liver and kidneys were evaluated. Three overfeeding techniques were used: (1) feeding a high fat diet, (2) reducing litter size, (3) force-feeding from 1-24 days. The overfeeding technique which exerted the greatest effect on growth was feeding a high-fat diet. In comparison to OM rats that suckled dams fed the low-fat diet, body weight as well as organ weight, DNA, protein and lipid were significantly elevated in 24-day-old OM rats that suckled dams fed the high-fat diet. In comparison to OM rats not overfed, the organs of the rats fed the high-fat diet contained significantly more cells at both 24 and 105 days, except for the heart which by 105 days contained more protein, but not DNA. Liver weight and growth in S 5B/P1 rats was similar, regardless of dietary manipulation. Compared to S 5B/P1 rats that suckled dams fed the low-fat-diet, kidneys were 12 per cent larger at 24 days and 19 per cent larger at 105 days in rats that suckled dams fed the high-fat diet and were thereafter fed a high-fat diet. Hearts of the latter rats were larger than the former rats at 24 days, but not at 105 days.     

Energy available from corn oil is not different than that from beef tallow in high- or low-fiber diets fed to humans

The impact of the source of dietary fat and the level of dietary fiber on digestibility and energy metabolism were studied in human (six male, six female) volunteers. Subjects were divided into two diet treatment groups, high fiber [29.0 g total dietary fiber (TDF)/d] and low fiber (18.6 g TDF/d), for the duration of the study. Each participated in three, 2-wk controlled feeding periods. Either beef tallow (BT), corn oil (CO) or carbohydrate (CHO) was added (25% of diet energy) to a base diet in a three-way crossover study. Energy expenditure, substrate oxidation and digestibility determinations were conducted at the end of each period. The protein, fat and CHO digestibility of the base diet was significantly different between the fiber levels. The digestibility (high-fiber/low-fiber) averaged 82%, 90% for protein, 96% and 98% for fat. After adjusting for TDF, the CHO digestibility averaged 96% and was not different between fiber levels. The digestibility of the added CO and BT was 99.6 and 99.8% respectively, and was not significantly different between the fiber levels. No significant differences in 24-h energy expenditure existed nor the thermic effect of food due either to fiber level or between the CHO, BT or CO. Fat oxidation in subjects consuming the low-fiber diet was 14% higher (P < 0.03) with the BT treatment than with the CO treatment but not different in those that consumed the high-fiber diet. The energy value of the two fat sources was not different but their utilization by individuals near energy balance may lead to differences in long-term weight maintenance.     

Enhancement of experimental colon cancer by genistein

Several phytochemicals and micronutrients that are present in fruits and vegetables are known to exert cancer chemopreventive effects in several organs, including the colon. Among them, the soybean isoflavonoid genistein received much attention due to its potential anticarcinogenic, antiproliferative effects and its potential role in several signal transduction pathways. The present study was designed to investigate the effect of genistein on azoxymethane (AOM)-induced colon carcinogenesis and to study its modulatory role on the levels of activity of 8-isoprostane, cyclooxygenase (COX), and 15-hydroxyprostaglandin F2alpha dehydrogenase (15-PGDH) in the colonic mucosa and colon tumors of male F344 rats. At 5 weeks of age, groups of male F344 rats were fed control (AIN-76A) diet or a diet containing 250 ppm genistein. Beginning 2 weeks later, all animals except those in the vehicle-treated groups were given weekly s.c. injections of AOM (15 mg/kg body weight) for 2 successive weeks. All rats were continued on their respective dietary regimen for 52 weeks after AOM treatment and were then sacrificed. Colon tumors were evaluated histopathologically. Colonic mucosae and tumors were analyzed for COX, 15-PGDH, and 8-isoprostane levels. Administration of genistein significantly increased noninvasive and total adenocarcinoma multiplicity (P < 0.01) in the colon, compared to the control diet, but it had no effect on the colon adenocarcinoma incidence nor on the multiplicity of invasive adenocarcinoma (P > 0.05). Also, genistein significantly inhibited the 15-PGDH activity (>35%) and levels of 8-iosoprostane (50%) in colonic mucosa and in tumors. In contrast, genistein had no significant effect on the COX synthetic activity, as measured by the rate of formation of prostaglandins and thromboxane B2 from [14C]arachidonic acid. The results of this investigation emphasize that the biological effects of genistein may be organ specific, inhibiting cancer development in some sites yet showing no effect or an enhancing effect on the tumorigenesis at other sites, such as the colon. The inhibition of 8-isoprostane levels by genistein indicates its possible antioxidant potential, which is independent of the observed colon tumor enhancement, yet this agent may also possess several biological effects that overshadow its antioxidant potential. The exact mechanism(s) of colon tumor enhancement by genistein remain to be elucidated; it is likely that its colon tumor-enhancing effects may, at least in part, be related to inhibition of prostaglandin catabolic enzyme activities.     

Chemoprevention of prostate cancer: the Prostate Cancer Prevention Trial

The possible relationship between physeal diseases and physeal form prompted investigation of change in steepness of the physis in young foals. The distal and proximal aspects of the longbones were sawn sagittally in the right and frontally in the left bones. The slabs were washed to remove saw debris, arranged in order and inspected. The proximal physes had a flat or gently arched form, without obvious inclination. In the distal physes there were distinct inclinations. Inspection of an identical slab from the medial aspect of the distal radius of two series of foals of different breeds showed that the degree of inclination of the physis with respect to the long axis of the bone increased with age. In a further series of foals, the angle of inclination was measured from radiographs of identical sagittal and frontal slabs of the distal radius. A line drawn through the secondary spongiosa was produced to intersect a line drawn along the physis where it was mostly steeply inclined, and the angle measured. The angle decreased (physeal inclination increased) with increasing age, up to 35-90 days. The steepness in the lateral aspect of the physis was similar to that in the medial aspect, although evident in a different plane.     

A randomized comparison of two weight-reducing diets. Calorie counting versus low-fat carbohydrate-rich ad libitum diet

We compared the importance of rate of initial weight loss for long term outcome in obese patients and the efficacy of two different dietary weight maintenance programmes. An initial weight loss of 12.6 kg was achieved either by eight weeks low energy diet (2 MJ/day) (n = 21) or 17 weeks conventional hypocaloric, high protein diet (5 MJ/day) (n = 22) both supported by an anorectic compound (ephedrine 20 mg and caffeine 200 mg thrice daily). Weight loss rate had no effect on long-term weight maintenance. Randomisation to one year weight maintenance of either an ad lib, low fat, high carbohydrate diet or a fixed energy diet (< 8 MJ/day), both supported by reinforcement sessions 2-3 times monthly, resulted in a maintenance of 13.2 of initial 13.5 kg weight loss in the ad lib group versus 9.7 of 13.8 kg in the fixed energy intake group. At follow-up two years after the initial weight loss, 65% of the ad lib group and only 40% of the fixed energy intake group had maintained a weight loss of > 5 kg.     

Chemoprevention in head and neck cancer: basic science and clinical application

As cure rates in childhood acute lymphoblastic leukemia edge toward 80%, the focus of research is shifting to better means of identifying and treating resistant cases. This new emphasis has stimulated progress in several areas. Recent findings suggest that poor early responses to therapy and detection of minimal residual disease at the postremission induction period by immunologic methods are reliable indicators of an adverse prognosis warranting modification of treatment. In this regard, timely administration of intensified chemotherapy, including a second reinduction/intensification phase, may nullify the adverse prognosis conferred by a delayed response to induction therapy. Comparative analysis of survival outcomes in T-cell patients who received chemotherapy or cranial irradiation (12 Gy) to prevent overt leukemia in the central nervous system suggests that the latter modality should be retained for cases with leukocyte counts > 100 x 10(9)/L. Recent innovations in histocompatibility matching, prevention of graft-versus-host disease, and antiviral prophylaxis have enhanced the applicability of hematopoietic stem cell transplantation, making this procedure available to candidates lacking matched sibling donors. Finally, demonstration that acute lymphoblastic leukemia has an angiogenic phase in bone marrow raises the possibility of effective treatment with antiangiogenic agents, such as endostatin. Remaining challenges in the treatment of childhood leukemia include 1) the development of specific and more effective therapy for high-risk cases and 2) the reduction of long-term complications associated with intensive chemotherapy and cranial irradiation.     

Physical activity and colon cancer

Heart disease and cancer, the major causes of mortality and morbidity in Western countries, have common risk factors. Exercise appears to reduce the risk of cardiovascular disease, but its role with respect to primary prevention of cancer has not been emphasized. Here we evaluate the epidemiological studies dealing with exercise and colon cancer. Despite the fact that different methods of assessing the amount of typical exercise of individuals and the different types of physical activity measured (occupational and recreational), there is remarkably consistent evidence that people who are highly physically active could be at a reduced risk of cancer of the colon. An analysis of case-control and cohort studies suggests that exercise might reduce the risk, at least in men, by up to one-third. We conclude that exercise has been overlooked as a potentially useful, effective, and acceptable method for reducing the risk of colon cancer.     

Nutritional factors and colon cancer

During the last 2 decades, substantial progress has been made in understanding the relationship between dietary constituents and the development of colon cancer in man. Unlike studies of cancer among smokers and nonsmokers, nutritional epidemiologic studies are confronted with the inherent difficulty of assessing reasonably precise exposures. The lack of consistency between international correlation studies and case-control studies does not necessarily negate a dietary etiology of colon cancer because these inconsistencies may have arisen, at least in part, from methodological limitations. Some of these deficiencies in epidemiological studies of diet and cancer have been corrected; recent case-control studies demonstrated that high dietary fat is a risk factor for colon cancer development and that an overall increase in intake of foods high in fiber might decrease the risk for colon cancer. The results of epidemiologic studies may be assumed to present conservative estimates of the true risk for cancer associated with diet. The populations with high incidences of colon cancer are characterized by high consumption of dietary fat, which may be a risk factor in the absence of factors that are protective, such as whole-grain cereals and of other high fiber. Laboratory-animal model studies have shown that certain dietary lipids and fibers influence tumorigenesis in the colon. The data of metabolic epidemiological and laboratory-animal model studies are sufficiently convincing with respect to the enhancement of colon cancer by type of fat and protection by certain dietary fibers.     

Effect of high-fat and low-fat diets on voluntary energy intake and substrate oxidation: studies in identical twins consuming diets matched for energy density, fiber, and palatability

There remains controversy over the effects of dietary fat content on voluntary energy intake. Additionally, the question of whether there is a genetic susceptibility to overeating high-fat diets has not been resolved. To address these issues, we designed two diets: a low-fat diet providing approximately 20% of energy as fat and a high-fat diet with approximately 40% of energy as fat. The diets were matched for energy density, fiber, and palatability. In a two-phase, 18-d intervention study, voluntary energy intakes and macronutrient oxidation rates during the fasting and fed states were determined in seven pairs of identical male twins. In contrast with results of previous intervention studies, in which low-fat and high-fat diets were not matched for energy density and other associated variables, we observed no significant difference in voluntary energy intake between the low-fat and high-fat phases, and mean daily intakes were similar (10.3 and 10.7 MJ/d, respectively). Postprandial rates of fat oxidation tended to reflect fat intakes in the two dietary phases, thus helping to explain the lack of a difference in mean energy intakes. There was also a significant twin-pair similarity in differences in energy intakes between dietary phases (P = 0.013). These results suggest that dietary fat content does not have a major influence on voluntary energy intake when dietary variables usually associated with fat are controlled for and that there may be a familial influence on the effects of dietary fat content on energy intake.     

The influence of high- and low-fibre diets on the activity of piperazine against Oesophagostomum spp. in pigs

An in vivo study evaluated the effect of diet on the efficacy of piperazine against nodular worms of pigs. Twenty pigs, later allocated into five groups, were each infected (and 37 days later re-infected) with 3000 infective larvae of a mixed isolate of Oesophagostomum dentatum and Oesophagostomum quadrispinulatum. Beginning on day 23 post infection (p.i.), pigs in groups 1 and 2 were fed a low-fibre diet consisting of 70% barley flour and 30% protein concentrate, while pigs in groups 3, 4 and 5 were fed a high-fibre diet consisting of 55% barley flour, 21% oat-husk meal and 24% protein concentrate. On day 42 p.i., pigs in groups 1 and 3 were orally dosed with 200 mg piperazine dihydrochloride (Ascarex D, 53%) per kg bodyweight, the recommended dose, while pigs in group 4 were given 100 mg kg-1. Groups 2 and 5 served as non-treated controls for the respective dietary regimens. Eight days after treatment, the pigs were slaughtered and worms recovered from the caecum and large intestine (divided into five sections) and counted. The mean worm count reduction (WCR) in group 1 (full-dose piperazine with low-fibre diet) was 89.8%, while the high-fibre diet in group 3 increased the WCR to 99.4%. In group 4, where the pigs were fed the high-fibre diet and treated with only 100 mg piperazine kg-1, the WCR was 90.9%, identical to the "low fibre" group 1 treated with twice this piperazine dose. There was a zero efficacy recorded against immature worms in all three treated groups. The high-fibre diet improved the efficacy of piperazine against more pathogenic and generally more tolerant O. quadrispinulatum to 99.2% compared with 84.3% at the low-fibre diet.