Effect of melatonin on 1,2-dimethylhydrazine-induced intestinal tumors in rats

Fifteen doses of 21 mg/kg body weight of 1,2-dimethylhydrazine (DMH) were injected into 48 female rats at one-week intervals. Controls included 25 animals while 23 received 20 mg/l of melatonin with drinking water, 5 times a week, at night-time, for 6 months, beginning from the day of the first injection. Although malignancies of large bowel developed in all animals, multiple tumors in the melatonin group were significantly fewer than in the rats treated with DMH alone (6,0 and 9,9 respectively; p < 0,001). Similarly, melatonin treatment was followed by a significantly lower frequency of tumor development in the ascending colon as well as fewer multiple neoplasms of the ascending and descending colon. Melatonin was also shown to inhibit carcinogenesis in the small intestine. It is suggested that the antitumor effects of melatonin is due to its antioxidant properties.     

Surgical management of retinal detachments related to coloboma of the choroid

We examined the influence of extruded chickpeas and wheat relative to casein and wheat in a dimethylhydrazine (DMH)-induced colon tumor study in male Sprague-Dawley rats. The three diets, based on a modified AIN76 rodent diet with fat present at 10 g/100 g dry matter (DM), were as follows: casein with wheat starch (Cas/S) as control, casein with wheat (Cas/W) and chickpeas with wheat (CP/W). All diets were fed from 5 wk of age throughout the 28-wk study. At 28 wk, there was a significantly lower incidence of large intestinal tumors in rats fed Cas/W relative to those fed CP/W ( 11 vs. 56%, chi-square test, P = 0.018). The colonic tumor burden (tumors/tumor-bearing animal) was not different in Cas/W-fed and CP/W-fed rats (1 vs. 1.7), but the tumor mass index was significantly lower in the former group (0.22 vs. 1.21, P = 0.026). Rats fed the CP/W diet had significantly lower plasma cholesterol concentration (P < 0.01) than rats fed the other two diets. The cecal contents of rats fed the CP/W diet had significantly greater relative weights (46%, P < 0.05) than those of the Cas/W-fed rats; this was associated with higher concentrations of all short-chain fatty acids. Fecal analyses showed significantly (P < 0.05) higher concentrations of total fat (54%), total steroids (83%) and secondary bile acids (179%) in the CP/W-fed rats relative those fed Cas/W. There were higher concentrations of nitrogen in the feces of CP/W rats relative to the Cas/W-fed rats (84%, P < 0.05), associated with greater fecal weights (67%, P < 0.05). Although wheat and its fibers have been shown to be protective against DMH-induced cancers in rats, this was not the case in this study in which chickpeas (45 g/100 g diet) provided the protein and were an important source of soluble fiber. Elevated fat, secondary bile acid concentrations and/or nitrogenous compounds could be responsible for the increased colon tumorigenesis seen and may reflect a legume effect.     

Influence of diets containing high and low risk factors for colon cancer on early stages of carcinogenesis in human flora-associated (HFA) rats

Germ-free rats colonised with a human intestinal flora were fed diets containing high risk (HR) or low risk (LR) factors for colorectal cancer, and putative biomarkers were evaluated in the colonic mucosa; (i) proliferation, (ii) 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci and (iii) DMH-induced DNA damage. The HR diet was high in fat (45% of calories) and low in calcium and fibre, reflecting levels characteristic of typical western diets. The LR diet was low in fat (<5% of calories), and high in calcium and fibre. The nutrient/energy ratio of the two diets were similar. Mucosal crypt cell proliferation, assessed after microdissection, was higher on the LR diet (mean number of mitoses per crypt was 2.65 on the LR diet, and 1.62 on the HR diet; P < 0.05). Aberrant crypt foci (ACF) were assessed in the mucosa 12 weeks after DMH treatment. On the HR diet there were significantly more small ACF with 1 and 2 crypts per focus, but fewer ACF with 3, 5 and 7 or more crypts per focus. There was no significant difference in total ACF or the total number of crypts. The effect of diet on DNA damage in the colon was assessed in vivo by the comet assay. Animals were fed a HR or LR diet for 12 weeks before treatment with DMH or saline. For carcinogen-treated animals, DNA damage was significantly higher in colon cells from animals on the HR diet. On the LR diet both DNA damage and the induction of small ACF were reduced despite an increase in cell proliferation. The increase in large ACF on the LR diet may be attributable to elevated crypt cell proliferation possibly increasing crypt fission rates.     

Chemoprevention of azoxymethane-induced intestinal carcinogenesis by a novel synthesized retinoidal butenolide, 5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone, in rats

The present study was designed to investigate the modifying effects of dietary 5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone (KYN-54), a new synthetic retinoidal butenolide, during the post-initiation phase on azoxymethane (AOM)-induced rat intestinal carcinogenesis. The number of aberrant crypt foci (ACF) in rat colon, colonic ornithine decarboxylase (ODC) activity and bromodeoxy-uridine (BrdUrd) labeling index in rat colonic epithelium were also assessed. At 7 weeks of age, male F344 rats (except the KYN-54 alone and control groups) were given weekly s.c. injections of AOM at 15 mg/kg body wt for 3 weeks. Starting 1 week after the last injection of AOM, rats (except the control group) were fed a diet containing KYN-54 at concentrations of 100 or 200 p.p.m. throughout the experiment. All animals were necropsied at 32 weeks after the start of the experiment. Compared with the AOM alone group, KYN-54 at both doses reduced the incidence and multiplicity of tumors in entire intestine (small and large intestines). In the 200 p.p.m. KYN-54 fed group especially, tumor incidence and multiplicity in the entire intestine were lower compared with the AOM alone group (P < 0.005 and P < 0.05 respectively). Also, the number of ACF/cm2 colon in the groups of rats treated with AOM and KYN-54 at both doses were significantly lower than that of rats treated with AOM alone (P < 0.05). Colonic ODC activity and BrdUrd labeling index in the groups of rats treated with AOM and KYN-54 at both doses were slightly lower than those treated with AOM alone. KYN-54 at 200 p.p.m. significantly lowered BrdUrd labeling index induced by AOM (P < 0.005). These results suggest that KYN-54 might be a promising chemopreventive agent for intestinal neoplasia.     

Effect of oyster mushroom (Pleurotus ostreatus) on pathological changes in dimethylhydrazine-induced rat colon cancer

The effect of 5% of dried oyster mushroom (Pleurotus ostreatus) in the diet on the dimethylhydrazine (DMH)-induced colon carcinogenesis was studied in male Wistar rats. DMH in a dose of 20 mg/kg of body weight was applied to animals once a week during a period of 12 weeks. Mushroom diet was applied either after treatment with DMH for another 21 weeks or during the whole experiment. Mushroom diet reduced significantly the incidence of lymphoid hyperplasia foci when mushroom was supplemented during the whole experiment. Tumour lesions could be characterized either as carcinoma in situ, or as infiltrating adenocarcinoma. Mushroom diet did not affect significantly the incidence of tumours. Nevertheless, a reduction in total number of tumours was observed in both groups of animals fed mushroom diet. A significant reduction of the number of tumour foci of the type carcinoma in situ was observed in animals fed the oyster mushroom during the whole experiment. Also these animals had the significantly lower number of aberrant crypt foci. Mushroom diet reduced the ornithine decarboxylase activity in the colon and in the liver when oyster mushroom diet was administered during the whole experiment.     

Inhibition of development of N,N'-dimethylhydrazine-induced rat colonic aberrant crypt foci by pre, post and simultaneous treatments with 24R,25-dihydroxyvitamin D3

It has recently been reported that new vitamin D3 derivatives can exert inhibitory effects on colon carcinogenesis in rats. In the present study the chemopreventive potential of 24R,25-dihydroxyvitamin D3 (24R,25(OH)2vitamin D3) was assessed in a murine model of colon carcinogenesis. In experiment 1, male 6-week-old F344 rats were administered N,N'-dimethylhydrazine (DMH) 20 mg/kg s.c. once a week 4 times. The rats were fed 24R,25(OH)2vitamin D3 at 10 ppm in the diet prior to (pre), together with (simultaneous) or after (post) DMH treatment. Modifying effects were assessed using aberrant crypt foci (ACF), putative preneoplastic lesions, as the end point markers in this model of colon carcinogenesis. After 8 weeks, pre and more markedly simultaneous administration of 24R,25(OH)2vitamin D3 was found to have reduced the total numbers of ACF and significantly inhibited the development of foci. After 16 weeks, numbers of foci with > or = 4 crypts, which are more likely to progress to tumors, were significantly reduced. The most pronounced inhibition of ACF development was noted in rats fed the 24R,25(OH)2vitamin D3 after DMH administration. The reduction was particularly marked in the proximal colon. Blood levels of calcium were not significantly increased over the control levels in groups administered DMH and the vitamin. Immunohistochemical staining showed numbers of proliferating cell nuclear antigen-positive cells to be lower in the colonic epithelia of rats fed the vitamin D3 metabolite than in the controls. In experiment 2, the effect of 24R,25(OH)2vitamin D3 on the alterations in c-fos, c-myc and c-jun oncogene expression in response to DMH administration was examined by northern blot analysis. The early increase in expression of ornithine decarboxylase (ODC) activity was not altered by 24R,25(OH)2vitamin D3. The results suggest that 24R,25(OH)2vitamin D3 is a cancer chemopreventive agent which may suppresses DMH induction of lesions and their subsequent development via an antiproliferative action.     

Inhibitory effect of the non-steroidal anti-inflammatory drugs, indomethacin and piroxicam on 2-acetylaminofluorene-induced hepatocarcinogenesis in male ACI/N rats

The modifying effects of the non-steroidal anti-inflammatory drugs, indomethacin (IMC) and piroxicam (PC) on hepatocarcinogenesis induced by 2-acetylaminofluorene (AAF) were investigated in male ACI/N rats. Rats were divided into 6 groups: group 1 was fed a diet containing 200 ppm AAF for 16 weeks, starting at 6 weeks of age; group 2 was fed an AAF together with 130 ppm PC-containing diet; group 3 received an AAF diet and IMC (10 ppm) in their drinking water; group 4 was fed a PC diet alone; group 5 was given IMC alone; and group 6 served as controls. The PC diet, or the drinking water containing IMC, was given to the rats starting at 5 weeks of age until 1 week after the carcinogen exposure. At termination of the experiment (week 36), the incidences of iron-excluding altered liver cell foci (24.2 +/- 5.2/cm2) and liver cell tumors (1/10, 10%), and the tumor multiplicity (0.10/rat) in rats of group 2 were significantly smaller than those of group 1 (foci incidence, 42.6 +/- 6.7/cm2; tumor incidence, 10/10, 100%; and multiplicity, 4.00/rat) (P < 0.05). Similarly, the incidence of iron-excluding hepatocellular foci (27.4 < 1.2/cm2) and liver cell tumors (1/10, 10%) and the tumor multiplicity (0.10/rat) in rats of group 3 were significantly lower than those of group 1 (P < 0.05). There were no liver cell lesions (foci and neoplasms) in rats of groups 4, 5 and 6. Thus, PC and IMC inhibited the hepatocarcinogenesis induced by AAF when administered concurrently with the carcinogen and the results may indicate possible involvement of altered arachidonic metabolism in the initiation phase of AAF-induced liver carcinogenesis.     

Malignant degeneration of experimental ulcerative colitis of the rat following s.c. injection of 1,2-dimethylhydrazine (author's transl)

Animal experiments were performed to answer the question whether ulcerative colitis is predisposed to malignant degeneration. Male Wistar rats were given aqueous solutions of degraded Carrageenan (4%; w/v). After induction of ulcerative colitis, 1,2-Dimethylhydrazine (DMH; 132 mg/kg body weight) was applicated during a period of 7 weeks. 17 of 18 rats developed multiple adenocarcinomas in the distal colon 15 weeks after the last injection of DMH. The Carrageenan induced colitis was localized predominantly in the distal part of the large bowel. Only 3 rats of a control group of 18 animals exposed to DMH only showed carcinomas of the colon. The difference is proven significant (P less than 0.01). Carrageenan for itself caused no malignancy. The results of the experiments demonstrate that, during ulcerative colitis, the colon of the rat is more susceptible to induction of cancer than the intact one.     

Motor responsiveness of proximal and distal human colonic muscle layers to carbachol and neurotensin

A regional heterogeneity of the responsiveness to neurohumoral agents has been demonstrated in proximal and distal colon. The aim of this study was to compare the motor responsiveness of circular and longitudinal muscles from ascending and sigmoid colon to carbachol and neurotensin. Ascending colon circular muscle was more sensitive to carbachol than sigmoid colon circular muscle (P < 0.05). Moreover, the potency for the carbachol-stimulated contraction was greater in ascending colon circular than longitudinal muscle (P < 0.05). The potency for carbachol and neurotensin stimulations was similar in longitudinal and circular muscles of both sections, respectively. However, the ascending colon circular muscle had a greater potency to neurotensin than longitudinal muscle (P < 0.03). Longitudinal muscle was more sensitive to the effects of neurotensin in sigmoid than ascending colon (P < 0.01). On a molar basis, neurotensin was approximately fivefold more potent than carbachol in producing similar contractions. These data suggest that these agents stimulate human colon smooth muscle according to region and type of muscle layer.     

Relationship between the nature of mucus and crypt multiplicity in aberrant crypt foci in the rat colon

Aberrant crypt foci (ACF) induced in the distal colon of F344 male rats, 4, 8, 12 and 35 weeks after the first administration of 1, 2-dimethylhydrazine-2HCl (DMH) were examined to determine whether a correlation exists between the nature of goblet cell mucin and the number of crypts (crypt multiplicity) comprising the ACF. According to the ACF score calculated from the results of the qualitative observation of sulfomucins (SuMs) and sialomucins (SiMs), the ACF in the 4th week showed a weak correlation between the nature of the mucus and crypt multiplicity, and the ACF of each class showed similar mucous profiles. From the 8th week, a significant difference (P < 0.01) was recognized between the ACF consisting of 3 crypts or less and those consisting of 4 crypts or more. The proportion of crypts with SiM predominance showed a decrease in the 8th week in the ACF consisting of 1 crypt and in the 12th week in the ACF consisting of 2 or 3 crypts, implying a recovery tendency. The ACF consisting of more than 4 crypts showed little change over time, retaining the tendency of SiM predominance. Ulex europaeus agglutinin-I (UEA-I) lectin-positive crypts appeared in the ACF. This finding was significantly more prominent (P < 0.001) in the ACF with SiM predominance than in the ACF with SuM predominance at each experimental period, and in the 12th week after the first administration of DMH, the incidence of ACF with UEA-I-reactive mucin was decreased in the ACF groups consisting of 3 crypts or less, compared with the ACF groups consisting of 4 or more crypts. These results suggest that the biological quality of mucus in ACF consisting of 4 or more crypts is different from that in ACF consisting of 3 crypts or less. This difference should be considered when ACF are used as an intermediate biomarker of colon cancer.     

Factors in delays in discharge from acute-care psychiatry

We investigated the modifying effects of nabumetone, a relatively selective cyclooxygenase-2 inhibitor, and esculetin, a lipoxygenase inhibitor, on N-methyl-N-nitrosourea(MNU)-induced mammary carcinogenesis in female Sprague-Dawley rats. A total of 124 rats, 6 weeks old, were divided into 6 groups. At 50 days of age, groups 1, 2, and 3 were treated with MNU (50 mg/kg body weight) by subcutaneous injection. From the age of 8 weeks, groups 2 and 4 were given 0.03% nabumetone in the diet and groups 3 and 5 were given 0.03% esculetin in the diet. All rats were necropsied at the termination (25 weeks after the start of experiment). The incidence and multiplicity of neoplasms in group 2 were significantly smaller than those in group 1 (P < 0.005 and P < 0.001, respectively). The incidence of neoplasms in group 3 was also significantly smaller than that in group 1 (P < 0.05). These results indicate that the intake of nabumetone or esculetin during the time corresponding to the post initiation phase has a chemopreventive effect on MNU-induced mammary carcinogenesis in rats.     

Inhibition of azoxymethane-initiated colon tumor by bovine lactoferrin administration in F344 rats

The influence of bovine lactoferrin (bLF) on colon carcinogenesis was investigated in male F344 rats treated with azoxymethane (AOM). Following three weekly injections of AOM, the animals received 2 or 0.2% bLF for 36 weeks. No effects indicative of toxicity were noted, but significant reduction in both the incidence and number of adenocarcinomas of the large intestine was observed with both doses. Thus, the incidences of adenocarcinomas in the groups receiving 2% and 0.2% bLF were 15% and 25%, respectively, in contrast to the 57.5% control value (P < 0.01 and P < 0.05, respectively). The results indicate that bLF might find application for chemoprevention of colon cancer.     

When the benefit is in doubt, who decides?

Female CBA mice were injected 1 mg/kg diethylstilbestrol (DES) on day 17 of gestation. Their male progeny received 15 weekly injections of 1,2-dimethylhydrazine (DMH) starting from the age of 2 months. Prenatal treatment with DES was followed by a significant acceleration and higher frequency of DMH-induced renal adenomas and renal capsule sarcomas in males. Tumor-induction was significantly enhanced by androgen effect. This was matched by a higher frequency of induced tumors of the large bowel. The increased frequency of androgen-dependent renal malignancies, served as indirect evidence of hyperandrogenization being stimulated in CBA male mice by prenatal treatment with DES.     

Abdominal wound tumor recurrence after open and laparoscopic-assisted splenectomy in a murine model

PURPOSE: The cause of abdominal wall tumor recurrences after laparoscopic surgery for cancer remains unknown. A recent study from our laboratory using a murine splenic tumor model suggests that poor surgical technique (i.e., crushing of the tumor) and not the CO2 pneumoperitoneum is responsible for port wound tumors. However, in that experiment no actual laparoscopic procedure or manipulation was performed. The purpose of the current study was to determine the rate of abdominal wound tumors after laparoscopic-assisted splenectomy performed via a CO2 pneumoperitoneum vs. open splenectomy using the mouse splenic tumor model. METHODS: To establish splenic tumors, female BALB/c mice (N=72) were given subcapsular splenic injections of a 0.1-ml suspension containing 10(5) C-26 colon adenocarcinoma cells via a left flank incision at the initial procedure. Eight days later, animals were randomized into one of two groups: 1) laparoscopic-assisted splenectomy, or 2) open splenectomy. Laparoscopic-assisted splenectomy animals had three laparoscopic ports placed and then underwent laparoscopic mobilization of the spleen under a CO2 pneumoperitoneum followed by extracorporeal splenectomy via a subcostal incision. Group 2 animals underwent open splenectomy via a subcostal incision after three port incisions were made in the same locations as for laparoscopic-assisted splenectomy mice. The incision was closed after 20 minutes in both groups. Ten days later, the mice were killed and inspected for abdominal wall tumor implants. The experiment was performed via two separate trials. RESULTS: When results of the two trials were combined, there was no significant difference in the incidence of animals in each group with at least 1 port tumor (open, 21 percent; laparoscopic-assisted splenectomy, 33 percent; P=0.14). However, the overall incidence of port site tumors (number of ports with tumors/total number of ports for each group) was significantly higher in the laparoscopic-assisted splenectomy group than in the open group (20 vs. 7 percent; P=0.01). The subcostal incisional tumor recurrence rate was also higher in the laparoscopic-assisted splenectomy group (50 vs. 21 percent; P=0.02). as was the perioperative mortality rate (21 vs. 7 percent; P=0.08). Results of the two individual trials were also considered separately. The incidence of port wound tumors decreased significantly from the first to the second laparoscopic-assisted splenectomy trial (36 vs. 9 percent; P=0.003), although the incidence of tumors at the subcostal incision and the mortality rate for the two laparoscopic-assisted splenectomy group trials were not significantly different. The open group tumor incidences did not change from trial to trial. CONCLUSIONS: Overall, significantly more port and incisional tumors were noted in the laparoscopic-assisted group. Although not statistically significant, mortality rate of the laparoscopic-assisted group was higher than the open group. The reasons for these findings are unclear. Laparoscopic mobilization was quite difficult and required excessive splenic manipulation, which may have liberated tumor cells from the primary tumor and facilitated port tumor formation. With increased experience, less manipulation was required to complete mobilization. Of note, the incidence of port tumors in the laparoscopic-assisted splenectomy group decreased significantly from the first to the second trials; therefore, it is possible that surgical technique is a factor in port tumor formation. However, the persistently high tumor incidence at the subcostal incision site argues against the hypothesis that the second trial's laparoscopic mobilizations were less traumatic. The CO2 pneumoperitoneum may also be a factor. Further studies are warranted to clarify these issues.     

Enhancement by the tricyclic antidepressant, desipramine, of experimental carcinogenesis in rat colon induced by azoxymethane

The effects of the tricyclic antidepressant drug desipramine on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on the serum norepinephrine (NE) concentration and the labeling index of colon mucosa were investigated in Wistar rats. Rats were treated s.c. with 7.4 mg AOM/kg body wt once a week for 10 weeks, and also s.c. with 10 mg desipramine hydrochloride (desipramine)/kg body weight until the end of the experiment. Treatment with desipramine significantly increased the incidence, but not the number, of colon tumors in week 35. However, it did not influence the location and the histological appearance of the colon tumors or the histological types of colon adenocarcinomas. Furthermore, it significantly increased the serum NE level and the labeling index of colon mucosa during and after AOM treatment. These findings indicate that desipramine enhanced the development of colon tumors and that its effect may be related to its effect in increasing proliferation of colon epithelial cells.     

The nonfermentable dietary fiber lignin alters putative colon cancer risk factors but does not protect against DMH-induced colon cancer in rats

The effect of supplementation of the diet with autohydrolyzed lignin on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis was studied using 112 male Sprague-Dawley rats. Rats received eight weekly injections of DMH (9.5 mg/kg s.c.) or the saline vehicle solution and then were maintained on a basal AIN-76 fiber-free diet or the basal fiber-free diet plus 5% or 10% (wt/wt) lignin for 24 weeks. Rats were killed 32 weeks after the start of the experiment. Colon tumor incidence, location, and multiplicity were determined. Body weight, caloric intake, fecal dry weight, gut transit time, pH of cecal contents, and total fecal bile acid excretion were measured. Supplementation of the diet with 5% or 10% lignin resulted in increased fecal dry weight and total fecal bile acid excretion and in decreased gut transit time, colon pH, and fecal bile acid concentration. Dietary lignin did not significantly affect colon tumor incidence or multiplicity compared with the fiber-free diet. Thus dietary supplementation with autohydrolyzed lignin, a food fiber with good bulking characteristics, had a significant effect on several factors that have previously been linked to reduction of colon cancer risk, but the consumption of high levels of lignin did not decrease the risk for colon cancer.     

Citrus auraptene exerts dose-dependent chemopreventive activity in rat large bowel tumorigenesis: the inhibition correlates with suppression of cell proliferation and lipid peroxidation and with induction of phase II drug-metabolizing enzymes

In our previous short-term experiment, Citrus auraptene inhibited the development of azoxymethane (AOM)-induced aberrant crypt foci, which are precursor lesions for colorectal carcinoma. In the present study, the possible inhibitory effect of dietary administration of auraptene was investigated using an animal colon carcinogenesis model with a colon carcinogen AOM. Male F344 rats were given s.c. injections of AOM (15 mg/kg body weight) once a week for 3 weeks to induce colon neoplasms. They also received diets containing 100 or 500 ppm auraptene for 4 weeks in groups of "initiation" feeding, starting 1 week before the first dosing of AOM. The diets containing auraptene were also given to rats for 38 weeks in groups of "postinitiation" feeding. At the termination of the study (38 weeks), dietary administration of auraptene caused dose-dependent inhibition in AOM-induced large bowel carcinogenesis. Auraptene feeding during the initiation phase reduced the incidence of colon adenocarcinoma by 49% at 100 ppm (P = 0.099) and 65% at 500 ppm (P = 0.0075). Auraptene administration during the postinitiation phase inhibited the incidence of colon adenocarcinoma by 58% at 100 ppm (P = 0.021) and 65% at 500 ppm (P = 0.0075). Also, the multiplicity of colon carcinoma was significantly reduced by initiation feeding at a dose level of 500 ppm (P < 0.01) and postinitiation feeding at a level of 100 and 500 ppm (P < 0.05 and P < 0.01, respectively). Feeding of auraptene suppressed the expression of cell proliferation biomarkers (ornithine decarboxylase activity and polyamine content) in the colonic mucosa and reduced the production of aldehydic lipid peroxidation [malondialdehyde and 4-hydroxy-2(E)-nonenal]. In addition, auraptene increased the activities of Phase II drug-metabolizing enzymes (glutathione S-transferase and quinone reductase) in the liver and colon. These findings suggest that the inhibitory effects of auraptene on AOM-induced colon tumorigenesis at the initiation level might be associated, in part, with increased activity of Phase II enzymes, and those at the postinitiation stage might be related to suppression of cell proliferation and lipid peroxidation in the colonic mucosa.     

Inferior ST segment depression as a useful marker for identifying proximal left anterior descending artery occlusion during acute anterior myocardial infarction

To determine whether or not ST segment deviation on admission electrocardiograms can identify patients with anterior acute myocardial infarction due to proximal left anterior descending artery occlusion, the magnitude and location of ST segment elevation or depression were compared between patients with proximal left anterior descending artery occlusion (group A, n = 47) and those with distal left anterior descending artery occlusion (group B, n = 59). ST segment depression in each of the inferior leads was significantly greater in group A than in group B. The incidence of ST segment depression > or = 1 mm in each of the inferior leads (II; 81% vs 27%, III; 85% vs 54%, aVF; 87% vs 47%, P < 0.01) was significantly higher in group A than in group B. In addition, the incidence of ST segment depression > or = 1 mm in all of the inferior leads was significantly greater in group A than in group B (77% vs 22%, P < 0.01). In group A, maximal ST segment elevation was more frequent in lead V2 alone (43% vs 14%, P < 0.01). Group A had greater ST segment elevation in lead aVL than group B, and the incidence of ST segment elevation > or = 1 mm in lead aVL was significantly higher in group A than in group B (66% vs 47%, P < 0.05). ST segment depression > or = 1 mm in all of the inferior leads was most valuable for identifying group A patients (77% sensitivity and 78% specificity). In contrast, the maximal ST segment elevation in lead V2 alone or ST segment elevation > or = 1 mm in lead aVL had a low diagnostic value (43% sensitivity and 86% specificity, 66% sensitivity and 53% specificity, respectively). In conclusion, this study indicates that analysis of ST segment deviation in the inferior leads is useful for identifying patients with acute anterior myocardial infarction due to proximal left anterior descending occlusion.     

Electrophysiological characteristics of submucosal neurones in the proximal colon of guinea-pigs: comparisons with caecum and descending colon

A systematic examination has been made of the active and passive electrophysiological properties and synaptic inputs of forty-four randomly impaled submucosal neurones in the proximal colon of the guinea-pig to compare these characteristics directly with those of submucosal neurones in the caecum (n = 70) and descending colon (n = 45). Within each of the three electrophysiological classes of submucosal neurones identified (S, S/AH and AH), no statistically significant regional differences were found with respect to the resting membrane potential, membrane time constant or input resistance between neurones of the proximal colon, descending colon and caecum. Of submucosal neurones from the proximal colon, forty-three of forty-four (98%) received fast excitatory synaptic potentials (fast EPSPs); thirty-nine (91%) were S neurones and the others were S/AH neurones; only one of the forty-four cells (2%) was an AH neurone. An idazoxan-sensitive slow inhibitory postsynaptic potential (slow IPSP) was induced in thirty of forty-three S and S/AH neurones (70%) of the proximal colon, compared with sixty-one of sixty-six caecal neurones (92%) and twelve of forty-one neurones (29%) in the descending colon. The mean (+/- S.E.M.) amplitude of the slow IPSP in proximal colonic neurones was 17 +/- 1 mV (range, 6-30 mV; n = 30), compared with the significantly larger synaptic response (25 +/- 1 mV; range, 7-38 mV; n = 66; P < 0.05) recorded in the caecum; the mean slow IPSP amplitude in the descending colon was significantly smaller (12 +/- 2 mV; range, 5-27 mV; n = 12; P < 0.05) than that in the caecum. In the proximal colon and caecum, only those neurones with a slow IPSP had a hyperpolarizing response to noradrenaline, whereas about 50% of those neurons of the descending colon that lacked a slow IPSP were hyperpolarized by noradrenaline, acting via alpha 2-adrenoceptors. Thus, the electrophysiological characteristics of the submucosal neurones of the proximal colon more closely resemble those of the caecum than those of the descending colon, of which many do not have a functional noradrenergic synaptic input. Furthermore, the results confirm that there are fundamental regional differences in the guinea-pig large intestine with respect to the synaptic organization of submucosal neurones of particular electrophysiological classes.     

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.