Incidence and effects of Ha-ras codon 12 G-->A transition mutations in preneoplastic lesions induced by N-nitrosomethylbenzylamine in the rat esophagus.

N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis is an important model for squamous cell carcinoma of the human esophagus. In this model, previous studies have shown that the GGA-->GAA Ha-ras codon 12 mutation is present in the majority of papillomas. No other Ha-ras mutation has been identified. Studies using other models of chemical carcinogenesis suggest that Ha-ras activation has a critical role during tumor initiation. We have used laser-capture microdissection and polymerase chain reaction-restriction fragment length polymorphism analysis to study the role of codon 12 Ha-ras mutation at various stages of tumor development in the rat esophagus. Our results indicate that Ha-ras mutation was present infrequently (4.3%) in premalignant lesions. The incidence of Ha-ras mutation was high in papillomas (57.1%), however, and 50% of papillomas expressed mutant Ha-ras RNA message. Additionally, there was a linear trend correlating increased incidence of Ha-ras mutation with later papilloma stage. These data suggest the role of ras activation later in neoplastic development. To evaluate the potential mechanism of action by which Ha-ras contributes to promotion and progression in this model, we compared mRNA expression of cyclin D1 and p27 in Ha-ras mutant and Ha-ras normal papillomas. We found no differences in mRNA expression of either cyclin D1 or p27 between these two papilloma populations. Our data suggest an important paradigm shift for the role of ras mutations in this model of chemical carcinogenesis, indicating a functional role of Ha-ras activation in promotion/progression and not in the initiation phase of NMBA-induced papillomagenesis.

Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries.

Fruit and vegetable consumption has consistently been associated with decreased risk of a number of aerodigestive tract cancers, including esophageal cancer. We have taken a "food-based" chemopreventive approach to evaluate the inhibitory potential of lyophilized black raspberries (LBRs) against N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in the F344 rat, during initiation and postinitiation phases of carcinogenesis. Anti-initiation studies included a 30-week tumorigenicity bioassay, quantification of DNA adducts, and NMBA metabolism study. Feeding 5 and 10% LBRs, for 2 weeks prior to NMBA treatment (0.25 mg/kg, weekly for 15 weeks) and throughout a 30-week bioassay, significantly reduced tumor multiplicity (39 and 49%, respectively). In a short-term bioassay, 5 and 10% LBRs inhibited formation of the promutagenic adduct O(6)-methylguanine (O(6)-meGua) by 73 and 80%, respectively, after a single dose of NMBA at 0.25 mg/kg. Feeding 5% LBRs also significantly inhibited adduct formation (64%) after NMBA administration at 0.50 mg/kg. The postinitiation inhibitory potential of berries was evaluated in a second bioassay with sacrifices at 15, 25, and 35 weeks. Administration of LBRs began after NMBA treatment (0.25 mg/kg, three times per week for 5 weeks). LBRs inhibited tumor progression as evidenced by significant reductions in the formation of preneoplastic esophageal lesions, decreased tumor incidence and multiplicity, and reduced cellular proliferation. At 25 weeks, both 5 and 10% LBRs significantly reduced tumor incidence (54 and 46%, respectively), tumor multiplicity (62 and 43%, respectively), proliferation rates, and preneoplastic lesion development. Yet, at 35 weeks, only 5% LBRs significantly reduced tumor incidence and multiplicity, proliferation indices and preneoplastic lesion formation. In conclusion, dietary administration of LBRs inhibited events associated with both the initiation and promotion/progression stages of carcinogenesis, which is promising considering the limited number of chemopreventives with this potential.

Inhibition of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus by dietary freeze-dried strawberries.

In the present study, we examined the ability of dietary freeze-dried strawberries to inhibit N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus. Initially, we conducted a bioassay to determine the effects of dietary freeze-dried strawberries on esophageal tumor development. Two weeks prior to NMBA treatment, animals were placed on a control diet or diets containing 5 and 10% freeze-dried strawberries. NMBA treatment was once per week for 15 weeks. At 30 weeks, 5 and 10% freeze-dried strawberries in the diet caused significant reductions in esophageal tumor multiplicity of 24 and 56%, respectively. Based on these results, we conducted studies to determine potential mechanisms by which freeze-dried strawberries inhibit tumorigenesis. In a short-term bioassay, we evaluated the effects of dietary freeze-dried strawberries on the formation of O6-methylguanine in the rat esophagus. Animals were placed on control diet or diets containing 5 and 10% freeze-dried strawberries for two weeks. At the end of this period, animals received a single subcutaneous dose of NMBA and were killed 24 h later. A significant decrease in O6-methylguanine levels was observed in the esophageal DNA of animals fed strawberries, suggesting that one or more components in strawberries influence the metabolism of NMBA to DNA-damaging species. Finally, in order to evaluate post-initiation effects, we conducted a study where freeze-dried strawberries were administered in the diet only following NMBA treatment. Animals were placed on control diet and dosed with NMBA three times per week for 5 weeks. Immediately following NMBA treatment, animals were placed on control diet or diets containing 5 and 10% freeze-dried strawberries. At 25 weeks, 5 and 10% freeze-dried strawberries in the diet significantly reduced tumor multiplicity by 38 and 31%, respectively. Our data suggest that dietary freeze-dried strawberries effectively inhibit NMBA-induced tumorigenesis in the rat esophagus.

Effects of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2'-deoxyguanosine levels in the Fischer 344 rat.

This study examined the effects of lyophilized black raspberries (BRB) on azoxymethane (AOM)-induced aberrant crypt foci (ACF), colon tumors, and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in male Fischer 344 rats. AOM was injected (15 mg/kg body wt i.p.) once per week for 2 wk. At 24 h after the final injection, AOM-treated rats began consuming diets containing 0%, 2.5%, 5%, or 10% (wt/wt) BRB. Vehicle controls received 5% BRB or diet only. Rats were sacrificed after 9 and 33 wk of BRB feeding for ACF enumeration and tumor analysis. ACF multiplicity decreased 36%, 24%, and 21% (P < 0.01 for all groups) in the 2.5%, 5%, and 10% BRB groups, respectively, relative to the AOM-only group. Total tumor multiplicity declined 42%, 45%, and 71% (P < 0.05 for all groups). Although not significant, a decrease in tumor burden (28%, 42%, and 75%) was observed in all BRB groups. Adenocarcinoma multiplicity decreased 28%, 35%, and 80% (P < 0.01) in the same treatment groups. Urinary 8-OHdG levels were reduced by 73%, 81%, and 83% (P < 0.01 for all groups). These results indicate that BRB inhibit several measures of AOM-induced colon carcinogenesis and modulate an important marker of oxidative stress in the Fischer 344 rat.

Failure of dietary lyophilized strawberries to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-and benzo[a]pyrene-induced lung tumorigenesis in strain A/J mice.

In the present study, we examined the ability of lyophilized strawberries in the diet to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- and benzo[a]pyrene (B[a]P)-induced lung tumorigenesis in the A/J mouse. Groups of 20 mice were administered purified AIN-76A diet containing 10% lyophilized strawberries 1 week before carcinogen dosing, and for the duration of the study. NNK was administered by i.p. injection in five, 0.414 mg doses. B[a]P was administered by gavage in five, 0.2 mg doses. At 20 weeks, there were no significant differences in tumor incidence or tumor multiplicity between the NNK+10% lyophilized strawberry group and the NNK control group. Similarly, at 24 weeks, there were no differences in tumorigenesis between the B[a]P+10% lyophilized strawberry group and the B[a]P control group. Therefore, lyophilized strawberries at 10% in the diet failed to inhibit NNK- and B[a]P-induced mouse lung tumorigenesis.

Isothiocyanates and freeze-dried strawberries as inhibitors of esophageal cancer.

A group of arylalkyl isothiocyanates were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by the esophageal-specific carcinogen, N-nitrosomethylbenzylamine (NMBA) in the F344 rat esophagus. Phenylpropyl isothiocyanate (PPITC) was more potent than either phenylethyl isothiocyanate (PEITC) or benzyl isothiocyanate (BITC). Phenylbutyl isothiocyanate (PBITC), however, had a lesser inhibitory effect on esophageal tumorigenesis, and phenylhexyl isothiocyanate (PHITC) actually enhanced esophageal tumorigenesis. Thus, the two- and three-carbon isothiocyanates were more effective inhibitors of NMBA-esophageal carcinogenesis than the longer chain isothiocyanates. The effects of the isothiocyanates on tumorigenesis were well correlated as to their effects on DNA adduct formation. The most likely mechanism of inhibition of tumorigenesis by these isothiocyanates is via inhibition of the cytochrome P450 enzymes responsible for the metabolic activation of NMBA in rat esophagus. A freeze-dried strawberry preparation was also evaluated for its ability to inhibit NMBA-esophageal tumorigenesis. It proved to be an effective inhibitor, although not as potent as either PEITC or PPITC. The inhibitory effect of the berries could not be attributed solely to the content of the chemopreventive agent, ellagic acid, in the berries.

Sulindac sulfone induced regression of rectal polyps in patients with familial adenomatous polyposis.

Sulindac sulfone (Exisulind), a metabolite of the non-steroidal anti-inflammatory drug, sulindac, was evalauted for its effects on the development of rectal polyps in patients with familial adenomatous polyposis. Three cohorts of 6 patients each were given doses of 200, 300, or 400 mg Exisulind twice daily. Hepatotoxicity, shown by elevation in blood transaminase levels, was the dose-limiting toxicity and occurred at the 400 mg bid dose. Due to this toxicity, all patients treated with the 400 mg dose were subsequently reduced to the 200 mg dose level. Subsequently, 2 of the 6 patients were dose-escalated to 400 mg bid dose. The patients were treated with Exisulind for a period of six months. Sixteen of 18 patients had regression of small polyps (> or = 6 mm in diameter) characterized by a flattening of the polyps and a macular "halo" appearance. Histopathologic examination of the polyp biopsy specimens showed a marked increase in the proportion of mucin producing cells in the glands after treatment with Exisulind at all dose levels. Ki-67 staining, a measure of cell proliferation, was higher in the polyps than in normal mucosa. There was no significant change in the proliferation index between baseline and six month values in any of the groups treated with Exisulind or in normal tissues. The median apoptotic labeling index, as determined by the TUNEL technique, was higher in the polyps than in normal-appearing mucosa. Overall, there was no significant change in the apoptotic labeling index between base-line and 6 months in normal-appearing mucosa however, the index in polyps was increased. These results suggest that treatment of FAP patients with Exisulind for a period of six months may lead to regression of small polyps, and that the mechanisms of Exisulind--induced regression appear to be through stimulation of mucus differentiation and apoptosis in glandular epithelium.

Inhibition of N'-nitrosonornicotine-induced esophageal tumorigenesis by 3-phenylpropyl isothiocyanate.

The ability of dietary isothiocyanates to inhibit the esophageal metabolism of N'-nitrosonornicotine (NNN) was examined in F344 rats. Following feeding of benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), 4-phenylbutyl isothiocyanate (PBITC) or 6-phenylhexyl isothiocyanate for 2 weeks, rats were killed and the esophagi were incubated in vitro with [5-3H]NNN. While dietary BITC, PEITC and PBITC all decreased NNN metabolism, dietary PPITC had the greatest effect, yielding inhibition ranging from 55 to 91% of the control production of various NNN metabolites. To determine the chemopreventive efficacy of PPITC on NNN-induced esophageal tumorigenesis, rats were fed AIN-76A diets containing 0, 1.0 or 2.5 micromol/g PPITC and were given untreated drinking water or drinking water containing 5 p.p.m. NNN. After 87 weeks, the experiment was terminated and the esophageal tumors were counted. Rats that were given untreated drinking water developed no tumors. Rats that were given 5 p.p.m. NNN and unadulterated AIN-76A diet had an esophageal tumor incidence of 71% and a multiplicity of 1.57 tumors/animal. The two dietary concentrations of PPITC reduced the incidence and multiplicity of NNN-induced esophageal tumors by >95%. These results demonstrate the remarkable chemopreventive efficacy of PPITC in the NNN-induced esophageal tumor model.

Definition of agitation following traumatic brain injury: I. A survey of the Brain Injury Special Interest Group of the American Academy of Physical Medicine and Rehabilitation.

OBJECTIVE: To determine national patterns of defining agitation after traumatic brain injury (TBI) by physiatrists with expressed interest in treating TBI survivors. DESIGN: A random sample of 70% of the members of the Brain Injury Special Interest Group (SIG) of the American Academy of Physical Medicine and Rehabilitation (AAPM&R) were surveyed by telephone. RESULTS: The 129 members who responded yielded an 82% response rate. Respondents rated 18 characteristics from established rating scales on a 5-point scale according to each characteristic's relation to its clinical definition of agitation. Physical aggression, explosive anger, increased psychomotor activity, impulsivity, verbal aggression, disorganized thinking, perceptual disturbances, and reduced ability to maintain or appropriately shift attention were rated by at least 50% of the sample as very important or essential to agitation. Delirium, as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM), has been proposed as a standard definition of agitation. The degree to which all characteristics from the 3rd revised edition of the DSM (DSM-IIIR), considered together, were perceived to relate to agitation predicted 24% of the degree to which the term "delirium" was perceived to relate to agitation (Canonical correlation r = .48, p = .0002). Physicians' ratings of individual delirium characteristics from the DSM-IIIR were examined to determine if a sufficient number were similarly ranked to fulfill the diagnostic criteria for delirium. A significant number of physicians rated diagnostic criteria for delirium in one direction, yet did not rank the term "delirium" accordingly (McNemar's p = .04). CONCLUSIONS: There is considerable variation among physiatrists in their rating of characteristics that define agitation. Many define agitation during the acute recovery phase as posttraumatic amnesia plus an excess of behavior such as aggression, disinhibition, and/or emotional lability. Less support was given to defining agitation by the DSM-IIIR or DSM-IV diagnostic criteria for delirium. Delirium appears related to, but is not sufficient for, a diagnosis of agitation.

Measurement and treatment of agitation following traumatic brain injury: II. A survey of the Brain Injury Special Interest Group of the American Academy of Physical Medicine and Rehabilitation.

OBJECTIVE: Determine national patterns of measuring and treating agitation after traumatic brain injury (TBI) by physiatrists with expressed interest in treating TBI survivors. DESIGN: A 70% random sample of members of the Brain Injury Special Interest Group of the American Academy of Physical Medicine and Rehabilitation was surveyed by telephone. MAIN OUTCOME MEASURE: The survey instrument was designed to determine the most common pharmacologic interventions for agitation and, where possible, match each drug with the target behavioral and cognitive characteristics for which it is prescribed. Data were also collected on the manner in which participants measured agitation and judged treatment efficacy. RESULTS: One hundred twenty-nine of 157 responded, yielding an 82% response rate. The majority of respondents were not measuring agitation in a standard fashion. The five most frequently prescribed drugs by the expert stratum were carbamazepine, tricyclic antidepressants (TCAs), trazodone, amantadine, and beta-blockers. In comparison, the nonexperts most often reported prescribing carbamazepine, beta-blockers, haloperidol, TCAs, and benzodiazepines. Desyrel (p = .06) and amantadine (p = .001) were significantly more likely to be chosen by experts than by nonexperts. Experts chose haloperidol significantly less often than nonexperts (p = .01). Prescription of sedating drugs such as haloperidol or benzodiazepines was not found to be associated with the acuity of injury of TBI patients in the respondent's practice, practice setting, or years of practice since completing residency. Choice of haloperidol to treat agitation was not significantly associated with the degree to which explosive anger, verbal aggression, or physical aggression were considered important to the respondent's definition of agitation. CONCLUSIONS: The majority of physiatrists surveyed did not formally measure agitation. Treatment strategies differ significantly between general physiatrists and those who specialize in the treatment of patients with TBI. The breadth of pharmacologic agents and strategies identified in this survey probably reflects the lack of research specific to the pathophysiology of the disorder of posttraumatic agitation.

Effects of theaflavins on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis.

The purpose of this experiment was to compare the inhibitory effects of the polyphenol fraction of black tea, theaflavins (TF), the polyphenol fraction of green tea, and (-)-epigallocatechin-3-gallate (EGCG) in the rat esophageal tumor model. The tea fractions were administered in the drinking water at concentrations of 360 and 1,200 ppm for two weeks before administration of the esophageal carcinogen N-nitrosomethylbenzylamine (NMBA). NMBA was administered subcutaneously in 10% dimethyl sulfoxide three times weekly for five weeks. Additional groups of rats received only vehicle and plain drinking water or vehicle and drinking water containing 1,200 ppm of each tea fraction. Twenty-five weeks after NMBA administration began, the experiment was terminated and esophagi were excised and scored for tumors. Rats that were not dosed with NMBA had no tumors. Rats treated with NMBA only had an esophageal tumor incidence of 100% and a multiplicity of 3.3 +/- 0.4 tumors/rat. The proportion of rats developing tumors was not significantly reduced by any of the four tea fractions at the concentrations tested. However, the 1,200 ppm concentrations of each tea fraction in the drinking water produced some reduction in esophageal tumor multiplicity, although only TF significantly reduced tumor multiplicity compared with rats treated with NMBA only. The rates of esophageal tumor formation were significantly reduced at 360 and 1,200 ppm by TF and EGCG.

Metabolites of a tobacco-specific nitrosamine, 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone (NNK), in the urine of smokeless tobacco users: relationship between urinary biomarkers and oral leukoplakia.

Two metabolites of the carcinogenic tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone were quantified in the urine of smokeless tobacco users. The metabolites are 4-(methylnitrosamino) -1-(3-pyridyl)-1-butanol (NNAL) and [4-(methylnitrosamino)-1-(3-pyridyl) but-1-yl]-beta-O-D-glucosiduronic acid (NNAL-Gluc). The study population consisted of 47 male nonsmokers, of whom 23 were snuff dippers, 13 were tobacco chewers, 3 were users of both products, and 8 were nonusers. The levels of NNAL-Gluc in urine ranged from 0.14-30.3 pmol/mg creatinine with a mean +/- SD of 3.47 +/- 5.86, whereas the levels of NNAL ranged from 0.02-8.73 pmol/mg creatinine with a mean +/- SD of 0.92 +/- 1.59. The mean levels of NNAL-Gluc and NNAL were not significantly different from those measured in a previous study of smokers. The levels of NNAL-Gluc were significantly higher in snuff dippers than in tobacco chewers. The ratio of NNAL-Gluc:NNAL was higher in snuff dippers than in tobacco chewers or smokers. There was no indication of two phenotypes of the NNAL-Gluc:NNAL ratio in smokeless tobacco users, in contrast to previous observations in smokers. Of the 39 smokeless tobacco users in this study, 16 presented with oral leukoplakia. When the total levels of NNAL-Gluc, NNAL, or NNAL-Gluc + NNAL were divided into tertiles, there was a significant association between the presence of leukoplakia and increasing levels of these metabolites; a similar relationship was found between urinary cotinine and leukoplakia. The results of this study demonstrate that there is significant uptake of carcinogenic nitrosamines in smokeless tobacco users, and that such products are not harmless alternatives to cigarettes. Moreover, the urinary biomarkers NNAL-Gluc, NNAL, and cotinine were associated with the presence of leukoplakia, which provides biochemical support for the role of smokeless tobacco products as a cause of oral leukoplakia.

Inhibition of metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by dietary benzaldehydes.

As part of a routine screening assay, benzaldehyde was found to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism. Consequently, the effects of benzaldehyde and several structurally related compounds on NNK metabolism were examined in murine hepatic and pulmonary microsomes. All test compounds inhibited formation of the metabolites 4-oxo-4-(3-pyridyl)butyric acid (OPBA), 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in hepatic microsomes and inhibited formation of 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK N-oxide), HPB, and NNAL in pulmonary microsomes. m-Anisaldehyde was the most potent inhibitor, and p-hydroxybenzaldehyde and syringaldehyde were less potent than benzaldehyde and vanillin in inhibiting the formation of OPBA and HPB, NNK metabolites that reflect metabolic activation (alpha-hydroxylation). Vanillin was essentially as potent as benzaldehyde. The mechanism of inhibition exhibited by these compounds appears to be competitive in nature. The ability of these compounds to inhibit NNK activation suggests that these compounds may be effective blocking agents (anti-initiating agents) for NNK lung tumorigenesis.

Enhancement of esophageal carcinogenesis in male F344 rats by dietary phenylhexyl isothiocyanate.

The purpose of this study was to evaluate the potential effects of dietary 6-phenylhexyl isothiocyanate (PHITC) on N-nitrosomethylbenzylamine (NMBA)-induced esophageal carcinogenesis in rats. Groups of 15 male F344 rats received weekly s.c. injections of NMBA in 20% dimethylsulfoxide or the vehicle alone for 15 consecutive weeks. Two weeks prior to initiation of carcinogen or vehicle injections rats were provided with modified AIN-76A diet or modified AIN-76A diet containing PHITC at levels of 0.4, 1.0 or 2.5 mumol/g diet. Experimental controls consisted of groups that received only the vehicle (vehicle controls), NMBA (carcinogen controls) or PHITC at the high dose level of 2.5 mumol/g diet. No esophageal tumors or preneoplastic lesions were detected in rats that received the vehicle or PHITC alone. In contrast, all rats treated with NMBA alone or PHITC + NMBA exhibited esophageal tumors and preneoplastic esophageal lesions. In groups that received PHITC + NMBA tumor multiplicity was increased by 21-69% when compared with rats treated with NMBA alone, indicating that PHITC enhanced esophageal tumorigenesis in this model system. These results, in conjunction with our previous work, demonstrate that arylalkyl isothiocyanates may inhibit or enhance esophageal tumorigenesis in the NMBA-treated rat. The ability of isothiocyanates to inhibit or enhance experimental tumorigenesis may depend on alkyl chain length of the isothiocyanate, the animal species examined and the specific carcinogen employed.

Failure of dietary oltipraz to inhibit benzo[a]pyrene-induced lung tumorigenesis in strain a mice.

Oltipraz (OLT), an antischistosomal agent, is known to inhibit tumorigenesis induced by a variety of carcinogens. In this study, we examined the ability of dietary oltipraz to inhibit benzo[a]pyrene (BP)-induced pulmonary adenoma formation in A/J mice. In a 6-week study, the maximum tolerated dietary concentration of OLT was found to be 450 ppm. Accordingly, OLT was tested at 0.8 MTD and 0.4 MTD. OLT diets were initiated 48 h prior to administration of a single i.p. dose of BP (100 mg/kg). Control or experimental diets were continued for the duration of the study. At 6 months, mice treated with BP only had a multiplicity of 9.0 tumors/animal and at 8.5 months, mice treated with BP only had a multiplicity of 21.4 tumors/animal. No inhibition of lung tumor formation by dietary OLT was observed at 6 or at 8.5 months after BP administration. In parallel experiments performed to assess the effects of OLT on pulmonary glutathione S-transferase activity, no induction of GST activity was found at the various time points examined. Doses of OLT that induced GST activity and inhibited tumorigenesis in mice in experiments conducted by other investigators would have exceeded the predetermined MTD for dietary OLT established in A/J mice in this study.

Effect of alkyl chain length on inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis and DNA methylation by isothiocyanates.

This study was undertaken to evaluate the inhibitory effects of benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC) or 4-phenylbutyl isothiocyanate (PBITC) on N-nitrosomethyl-benzylamine (NMBA)-induced esophageal tumorigenesis in male Fischer 344 rats. Groups of 15 male rats were fed modified AIN-76A diet or diet containing the four isothiocyanates at concentrations of 2.5, 1.0 and 0.4 mumol/g diet for 25 weeks. After two weeks, rats were administered 0.5 mg/kg NMBA s.c. once weekly for 15 weeks. Additional controls received modified AIN-76A diet only or diet containing the high concentration of isothiocyanates (2.5 mumol/g) only. No tumors were found in any of the groups that were not administered NMBA. Rats treated with NMBA only developed 6.7 +/- 0.8 tumors/animal. Tumor incidences in rats treated with 2.5 and 1.0 mumol PEITC/g diet, and with all three dietary concentrations of PPITC were inhibited by 60-100% compared to controls. Tumor multiplicities were inhibited by 83-100% by PEITC or PPITC at all dietary concentrations tested. PPITC clearly had a stronger inhibitory effect on NMBA tumorigenesis than did PEITC. Compared to PEITC and PPITC, BITC and PBITC had little inhibitory effect on tumor multiplicity and no effect on NMBA tumor incidence. In general, the occurrence of preneoplastic lesions (acanthoses, hyperkeratoses, leukoplakias and leukokeratoses) was inhibited in a similar manner as tumor incidence and multiplicity, except that no experimental diet resulted in a significant reduction of the incidence of acanthoses and hyperkeratoses.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary nitrogen and lipid utilization by growing pigs fed structured triacylglycerides synthesized from medium-chain triacylglycerides and menhaden oil.

A total of 24 crossbred barrows were used in a 19-d metabolism trial to determine the effect of dietary structured triacylglycerides synthesized by the random reesterification of medium-chain triacylglycerides (MCT) and menhaden oil on growth performance, nitrogen retention, and apparent digestibilities of nitrogen, lipid, and fatty acids. Pigs were randomly assigned to four dietary treatments differing only in lipid source. Dietary treatments (percentage by weight of total lipid) contained either 1) corn oil: soybean oil:MCT oil (40:10:50), 2) MCT oil:menhaden oil (60:40 as structured triacylglyceride), 3) MCT oil: menhaden oil (60:40 nonstructured, physical mixture), or 4) structured triacylglyceride (as in 2): safflower oil:canola oil (80:10:10). Total fecal and urine collections were conducted during two 5-d periods. Apparent nitrogen digestibility and nitrogen retention were high (> 95%) and not affected (P > .05) by dietary treatment. Apparent fatty acid digestibilities were affected by dietary lipid source. Palmitic and arachidonic acid digestibilities were lower (P < .05) for Diet 1, heptadecanoic acid digestibility was elevated by 21% (P < .05) for Diet 2 relative to Diet 3, and stearic acid digestibility was highest (P < .05) for Diet 1, followed by Diets 2, 3, and 4 in decreasing order. This study demonstrates that the physical nature of the lipid (structured vs nonstructured) affects fatty acid digestibility patterns in the growing pig. Further evaluation of MCT/menhaden oil structured triacylglyceride is needed.