Effects of perinatal stress on the anxiety-related behavior of the adolescence mouse.

We evaluated the effects of sound noise or forced swim stress applied to pregnant mice or to neonatal mice on the anxiety-related behavior using the elevated plus-maze test performed during the age of 5 weeks. The forced swim stress applied at the late gestation period, days 10-18 of pregnancy, caused a significant reduction of the body weight gain of the dams. However, the anxiety-related behavior of the male and female offspring were not affected by the antenatal stress treatment. When the forced swim stress was applied to the neonatal mice during the late lactation period, 14-18 days after birth, the male mice showed an elevated level of anxiolytic behavior accompanying the reduction of the emotion-related motor activity. The anxiety-related behavior of the female mice was not affected by the stress treatment. Furthermore, we applied the sound noise or forced swim stress to the neonatal mice immediately after the weaning, 21-25 days after birth. The stress applied after the weaning period had no effect on the anxiety-related behavior. These results suggested that the stress applied during the lactation period, but not that during the antenatal period, nor after the weaning period, might have gender-dependently reduced the anxiety level of the male mouse. It was shown that the effects of perinatal stress on the anxiety-related behavior of the adolescent mouse varied according to the period of application and gender. The hypothesis that gender-dependent abnormalities in neurodevelopment might be caused by the excess stress applied to the breast-fed infant is of importance in elucidating the relationship between the psychoneurotic disorder in childhood and the environment stress of the breast-fed infant.

Effects of (Z)-3-hexenol, a major component of green odor, on anxiety-related behavior of the mouse in an elevated plus-maze test and biogenic amines and their metabolites in the brain.

In the present study, the effect of (Z)-3-hexenol, one of the main constituent of green odor, on the anxiety-related behavior of mouse and the content of 5-hydroxytryptamine (5-HT), dopamine and their metabolites in the brain were investigated. Evaluation of anxiety-related animal behavior was performed by measuring the percent of time spent on the open arms and the percent of open-arm entries as conventional anxiety indices. The number of times displaying risk-assessment from a closed arm was also measured as an ethological anxiety index. Diazepam, an anxiolytic agent, enhanced the percent of time spent on the open arms and the percent of open-arm entries. The number of times displaying risk-assessment was not affected by diazepam in the present study. The percent of time on the open arms were depressed, and the number of times displaying risk-assessment were stimulated by 1-(3-trifluoromethylphenyl)piperazine (TFMPP), indicating that TFMPP acts as an anxiogenic agent. (Z)-3-Hexenol revealed anxiolytic activity and increased the percent of time spent on the open arms and decreased the number of times displaying risk-assessment. In the neurochemical study, diazepam had no effect on the content of 5-HT and its metabolite in the brain cortex or hippocampus. On the other hand, TFMPP inhibited the 5-HT turnover rate accompanied by the elevation of the 5-HT content and reduction of the 5-HIAA content in the brain cortex and hippocampus. (Z)-3-Hexenol significantly increased the 5-HT content without affecting the 5-HIAA content or the 5-HT turnover rate in the brain cortex or hippocampus. Changes in serotonergic activity in the cortex and hippocampus were suggested to be involved in the anxiolytic effect of (Z)-3-hexenol observed in the elevated plus-maze test.

Vascular endothelial growth factor is implicated in early invasion in cervical cancer.

The association between the expression of vascular endothelial growth factor (VEGF) and clinicopathological factors has scarcely been examined in cervical cancer. This study examines the level of VEGF messenger RNA (mRNA) expression in invasive cervical cancer and its association with clinicopathological features including microvessel density. The level of VEGF mRNA was assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) using beta-actin as an internal control in 66 patients with stages Ia-IVb invasive cervical cancer. In 42 patients who underwent surgery, the microvessel count was also assessed by immunostaining for factor VIII-related antigen in the most neovascularised area of the specimen. The highest level of VEGF mRNA expression was observed in early invasive cervical cancers. Except for stage IVb, the stage of the disease inversely correlated with the level of VEGF mRNA (P < 0.05). There was no significant difference in the level of VEGF mRNA with respect to histological cell types. 38 patients with stages Ib-IIb cervical cancer underwent radical hysterectomy and pelvic lymphadenectomy. There was no significant difference in the level of VEGF mRNA with respect to lymph node metastasis, depth of stromal invasion, tumour size, parametrial involvement or vaginal involvement among these patients. A significant relationship was found between the microvessel density and the level of VEGF mRNA (P < 0.01). These findings provide evidence that the expression of VEGF is involved in the promotion of angiogenesis in cervical cancer and plays an important role in early invasion.

Platelet-derived endothelial cell growth factor is not implicated in progression of cervical cancer.

We examined the expression of platelet-derived endothelial cell growth factor (PD-ECGF) mRNAs in 47 invasive cervical cancer tissues by semi-quantitative RT-PCR and addressed its association with clinicopathological features including microvessel density. Squamous cell carcinomas expressed higher levels of PD-ECGF mRNA than non-squamous cell carcinomas (P=0.014). We found no association between FIGO stage and levels of PD-ECGF mRNA. A subset of 31 patients with stage Ib-II cervical cancer underwent radical hysterectomy and pelvic lymphadenectomy. There were no significant differences in PD-ECGF mRNA levels with respect to tumor size, degree of stromal invasion, lymphvascular space involvement, parametrial involvement, vaginal involvement or lymph node metastasis among these patients. There was no correlation between microvessel density and the levels of PD-ECGF mRNA. These findings suggest that PD-ECGF expression is not associated with progression and metastasis of cervical cancer.

Serum C-reactive protein as a prognostic factor in patients with epithelial ovarian cancer.

OBJECTIVE: It is well known that the serum level of Interleukin-6 (IL-6) correlates with the level of C-reactive protein (CRP). The purpose of this study is to determine the significance of CRP as a prognostic factor in epithelial ovarian cancer. STUDY DESIGN: The present study is comprised of 120 patients with epithelial ovarian cancer from 1985 to 1992. In this study, CRP levels above 50 mg/l were considered high CRP. Univariate and multivariate analyses were performed to identify clinicopathological variables associated with poor survival. RESULTS: The serum CRP value was significantly associated with the volume of ascites (P = 0.000004). Univariate analysis showed that the FIGO stage, primary tumour diameter, size of residual tumour, histologic grade, volume of ascites and high serum level of CRP were significant prognostic factors. Cox's multivariate proportional hazard model showed that histologic grade was the most important prognostic factor (P = 0.0026). FIGO stage and volume of ascites were also independent factors for 5-year survival (P = 0.0310 and P = 0.0216, respectively). However, the serum CRP value was not an independent prognostic factor. CONCLUSION: CRP is an adverse prognostic factor in univariate analysis, but not in multivariate analysis.

CD44 exon v6 is not implicated in the progression and metastasis of endometrial cancer.

We examined the presence of mRNA for CD44v6 and assessed the association with clinicopathological features in 42 patients with endometrial cancer by RT-PCR and subsequent Southern blot hybridization with oligonucleotide probe specific for v6. The standard form of CD44 was expressed in all specimens and 20 out of 42 endometrial cancers expressed an isoform containing exon v6 in combination with other variant exons. However, there was no correlation between the expression of CD44v6 and any clinicopathological factors. These findings suggested that the expression of CD44v6 is not implicated in the progression and metastasis of endometrial cancer.

Different angiogenic pathways in human cervical cancers.

OBJECTIVE: The objective of this study is to clarify the association between the expression of two types angiogenic factors, vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase(dThdPase) and clinicopathological features, including tumor angiogenesis, in cervical cancers. METHODS: The expression of VEGF and PD-ECGF was evaluated by immunohistochemical staining of tumor specimens from 73 patients with stage Ib-IIb cervical cancer (51, squamous cell carcinoma; 19, adenocarcinoma; 3, adenosquamous carcinoma) who underwent radical hysterectomy. The microvessel density was assessed by immunostaining for factor VIII-related antigen in the most neovascularized area. RESULTS: The microvessel density in adenocarcinomas was significantly higher than that in squamous cell carcinomas (P < 0.01). The intensity of VEGF expression in adenocarcinomas was significantly stronger than that in squamous cell carcinomas (P < 0.05). In contrast, the expression of PD-ECGF in squamous cell carcinomas was significantly higher than that in adenocarcinomas (P < 0.0001) and adenosquamous carcinomas (P < 0.01). There was an inverse relationship between VEGF expression and PD-ECGF expression among all patients studied (P < 0.001). The microvessel density was significantly correlated with the intensity of VEGF expression (P < 0.05). In contrast, there was no correlation between the microvessel density and the expression of PD-ECGF. CONCLUSIONS: The expression of VEGF appears to be involved in the promotion of angiogenesis in cervical cancers. Furthermore, we propose that angiogenic pathways may be different in different types of cervical cancers.

CD44 exon v6 correlates with cellular differentiation but not with progression and metastasis of cervical cancer.

The purpose of this study was to investigate whether CD44v6 expression correlates with progression or metastasis of cervical cancer. The presence of mRNA for CD44v6 was examined, the association with clinicopathological features was assessed in 80 patients with cervical cancer by reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent Southern blot hybridisation with an oligonucleotide probe specific for v6. The standard form of CD44 was expressed in all specimens and 53 of 80 cervical cancers expressed an isoform containing exon v6 in combination with other variant exons. In addition, longer size transcripts of more than 1350 bp (long form) were identified in 22 of the 53 CD44v6 positive patients. The expression of CD44v6 and CD44v6 long form in squamous cell carcinomas was significantly higher than that in non-squamous cell carcinomas (P < 0.001). The expression of CD44v6 long form in histological grade 1 and 2 was significantly higher than that in grade 3 (P < 0.05). 47 patients in stage Ib-IIb cervical cancers were treated by radical hysterectomy and pelvic lymphadenectomy. We did not find any association between the expression of the long form or the short form of CD44v6 and any pathological features, except for histological cell type. These findings suggest that the regulation of CD44v6 seems to be different between different histological cell types and different tumour grades, and the expression of CD44v6 might not be implicated in the progression and metastasis of cervical cancer.

The expression of vascular endothelial growth factor and transforming growth factor-beta associates with angiogenesis in epithelial ovarian cancer.

The object of this study was to clarify the association between microvessel density and clinicopathologic factors, as well as the association of angiogenic factors (vascular endothelial growth factor [VEGF] and transforming growth factor-beta [TGF-beta]) with tumor angiogenesis and patient survival in epithelial ovarian cancer. The expression of VEGF and TGF-beta was evaluated by immunohistochemical staining in 60 patients with epithelial ovarian cancer. The microvessel density, assessed by immunostaining for factor VIII-related antigen in the most neovascularized areas, varied depending on histological types but not on International Federation of Gynecology and Obstetrics stage. Patients with stage III carcinomas and positive TGF-beta had more extensive peritoneal dissemination and a worse outcome. The microvessel density of VEGF-rich and TGF-beta positive tumors was significantly higher than that of VEGF-poor and TGF-beta negative tumors. Angiogenesis appears to be an early event in epithelial ovarian cancer and may be induced differently in tumors of different histological types. The expression of VEGF and TGF-beta associates with the promotion of angiogenesis, and the expression of TGF-beta is a prognostic indicator in epithelial ovarian cancers.

Placenta growth factor is abundantly expressed in human cervical squamous cell carcinoma.

Tumor angiogenesis is essential for solid tumor growth. The object of this study was to investigate the presence of newly identified angiogenic factor, placenta growth factor (P1GF) in human cervical cancers. The expression of P1GF mRNA was assessed by RT-PCR in 29 patients with cervical cancer. Fifteen out of 29 cervical cancers expressed a certain level of P1GF mRNA. In addition, the expression levels of P1GF mRNA in squamous cell carcinomas were significantly higher than those in adenocarcinomas. There was no correlation between the expression of P1GF mRNA and FIGO stage. These results indicate that the expression of P1GF may be implicated in the promotion of angiogenesis in human cervical squamous cell carcinomas, but not in human cervical adenocarcinomas.

Inhibition by gonadectomy of effects of 2-acetylaminofluorene in livers of male, but not female rats.

The influence of gonadectomy on the effects of 2-acetylaminofluorene (AAF) in the livers of rats was studied. Groups of male and female F344 rats at 9 weeks of age were given AAF by daily gavage 5 days per week for 4 or 8 weeks for total cumulative doses of 1.0 or 2.0 mmol/kg body wt. AAF was administered either with no pretreatment or beginning 4 weeks after gonadectomy, which was performed at 5 weeks of age. In male rats AAF induced a large number of placental glutathione S-transferase foci in livers by 8 weeks, while in female rats the number was about 10% of that in males. Orchidectomy decreased the AAF induction of foci in male rats by 60%, whereas ovariectomy had no effect in female rats. Similarly, orchidectomy decreased DNA adduct levels approximately 85% in male rats given AAF by gavage for 4 weeks. In ovariectomized female rats at 4 and 8 weeks hepatic DNA adduct levels were somewhat elevated (< 50%) as compared to intact controls. The zone of glutamine synthetase-positive hepatocytes around the central vein was reduced by AAF exposure of male, but not female, rats. Male rats displayed a larger zone than females and the zone in males was reduced to the level of females by orchidectomy. Orchidectomy also diminished the effect of AAF on glutamine synthetase-positive cells. Thus, the induction of neoplastic conversion by AAF in rat liver, the extent of DNA adduct formation and the reduction of the glutamine synthetase-positive zone of hepatocytes were greater in males than females and were dependent upon the hormonal status of males.

Dose response effects of 2-acetylaminofluorene on DNA damage, cytotoxicity, cell proliferation and neoplastic conversion in rat liver.

This study measured the effect of precise doses of 2-acetylaminofluorene (AAF) in inducing DNA damage, functional changes and neoplastic conversion in rat liver. Groups of male F344 rats at 9 weeks of age were exposed to cumulative doses of 0.5 or 2.0 mmol AAF per kg body weight given by gavage daily 5 days per week over an 8-week period and maintained with no further exposure for up to 8 weeks. Administration of AAF resulted in the formation of N-deoxyguanosin-(8-yl)-2-aminofluorene in liver DNA in relationship to dose. In centrilobular hepatocytes the zone of glutamine synthetase-expressing cells was reduced by exposure. By 8 weeks, but not at 4 weeks, the higher of the two doses of AAF provoked an increase in cell proliferation measured by immunohistochemical incorporation of bromodeoxyuridine. Altered hepatocellular foci expressing the placental form of glutathione transferase were induced by the high dose of AAF at 4 weeks, but not at the low dose. At 8 weeks the incidence of foci at the high dose was 79 times that induced by the low dose. These foci were highly proliferative. In animals exposed to AAF for 8 weeks and maintained for 4 weeks with no exposure, DNA adducts decreased by 80% and cell proliferation subsided by 80%, although the glutamine synthetase zone remained diminished. After discontinuation of AAF, the number of foci diminished by 50% and their proliferation subsided by 80% at 4 weeks, indicating a phenotypic reversion of many foci. With this protocol of administration of precise doses of AAF, we have established non-linearity of effects and a lack of correlation between DNA adduct formation and induction of cellular lesions. We suggest that doses in the range of those reported can be used to study the contribution of epigenetic and genotoxic effects in carcinogenesis and to study threshold events.

Inhibition of colon carcinogenesis by prostaglandin synthesis inhibitors and related compounds.

The inhibitory effect of 40 and 80% maximum tolerated dose (MTD) levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid on colon carcinogenesis was investigated in male F344 rats. The MTD levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid as determined in male F344 rats were 500, 500, 250 and 3000 p.p.m. respectively. At 5 weeks of age, groups of male F344 rats were fed the control (AIN-76A) diet and 40 and 80% MTD levels of each test agent in AIN-76A diet. At 7 weeks of age, all animals except the vehicle (saline)-treated controls received azoxymethane (AOM) at a dose rate of 15 mg/kg body wt, once weekly for 2 weeks. All animals were necropsied 50 weeks after the second AOM injection and colon tumor incidences were compared among the groups fed the control diet and chemopreventive agents. Animals fed 400 (80% MTD) and 200 p.p.m. (40% MTD) of piroxicam, 400 p.p.m. (80% MTD) of ibuprofen and 200 p.p.m. (80% MTD) of ketoprofen showed a significant inhibition of colon tumorigenesis as compared to those fed the control diet. Results analyzed by the linear regression method suggested a dose-dependent inhibition of colon carcinogenesis with increasing levels of piroxicam or ibuprofen. In contrast, glycyrrhetinic acid had no measurable chemopreventive effect on colon carcinogenesis.

Cell proliferation induced in the kidneys and livers of rats and mice by short term exposure to the carcinogen p-dichlorobenzene.

Cell proliferation in the kidneys and livers of rats and mice exposed short-term to p-dichlorobenzene (p-DCB) was evaluated by immunohistochemical measurement of bromodeoxyuridine (BrdU) incorporation into nuclei of DNA-synthesizing cells. p-DCB was given by gavage at two doses up to 600 mg/kg body weight for 4 days. The cumulative fraction of proliferating cells was increased in the proximal tubule epithelial cells of male rats at the high dose, but not at the low dose nor in females at either dose using gamma-glutamyl transferase reaction to identify tubular cells. Also, no increase in cell proliferation was found in mouse kidneys. The fractions of proliferating cells in the livers of rats and mice of both sexes were also increased. The increased cell proliferation in only male rat kidney and in the livers of mice of both sexes correlates with the reported carcinogenic effects of p-DCB in those tissues. However, the finding that p-DCB also induced cell proliferation in the livers of rats of both sexes, which were not a site of p-DCB-induced tumors in bioassays, and in female mice at the low dose, which was not affected by an increase in tumors, reveals a lack of concordance and indicates that acute induction of cell proliferation is not sufficient to lead to carcinogenesis.

Butylated hydroxytoluene lacks the activity of phenobarbital in enhancing diethylnitrosamine-induced mouse liver carcinogenesis.

The effect of the food additive butylated hydroxytoluene (BHT) as an enhancer of liver carcinogenesis in mice was investigated. Liver carcinogenesis was initiated by intraperitoneal injection of diethylnitrosamine (DEN) in male B6C3F1 mice at 100 or 200 mumol/kg body weight once a week for 10 weeks (total exposure 1000 or 2000 mumol/kg body weight). After an exposure-free recovery interval of 4 weeks, groups of mice were fed either basal diet or diets containing either 5000 ppm BHT or 500 ppm phenobarbital (PB), as a positive control, for 24 weeks. Exposure to the initiating doses of DEN alone induced no liver foci at 10 weeks or at 14 weeks after the recovery period, but at termination at 38 weeks, foci and adenomas were present in a dose-related incidence. In the groups given BHT after DEN/recovery, the incidence and the multiplicity of liver foci and adenomas were not different from those in mice given only DEN/recovery, whereas, in the groups given PB after DEN, liver lesions were increased by 1.7-3.0-fold. In conclusion, BHT had no promoting or syncarcinogenic effect on DEN-induced mouse liver carcinogenesis, whereas under the same conditions, PB acted as an enhancer.

Chemoprevention of colon carcinogenesis by dietary administration of piroxicam, alpha-difluoromethylornithine, 16 alpha-fluoro-5-androsten-17-one, and ellagic acid individually and in combination.

The chemopreventive action of 40 and 80% maximum tolerated dose (MTD) levels of piroxicam, D,L-alpha-difluoromethylornithine (DMFO), 16 alpha-fluoro-5-androsten-17-one (DHEA analogue 8354), and ellagic acid (EA) administered in diet individually and in combination before and during initiation and postinitiation phases of azoxymethane-induced neoplasia of the intestine was studied in male F344 rats. The MTD levels of piroxicam, DFMO, DHEA analogue, and EA were determined in male F344 rats and found to be 500, 5,000, 500, and 10,000 ppm, respectively, in modified AIN-76A diet. When these agents were fed in combination, the MTD levels were: piroxicam plus DFMO, 250 and 2500 ppm; piroxicam plus DHEA analogue, 250 and 250 ppm; piroxicam plus EA, 250 and 5000 ppm; piroxicam plus DFMO plus DHEA analogue, 250, 2500, and 250 ppm; and piroxicam plus DFMO plus EA, 250, 2500, and 5000 ppm. From these MTD values, 40 and 80% MTD levels were calculated and tested for their efficacy. At 5 weeks of age, animals were fed the modified AIN-76A (control) diet and experimental diets containing 40 and 80% MTD levels of piroxicam, DFMO, DHEA analogue, and EA individually and in combination. At 7 weeks of age, all animals except the vehicle-treated groups were administrated s.c. injections of azoxymethane (15 mg/kg body weight/week for 2 weeks). Animals intended for vehicle treatment received s.c. injections of an equal volume of normal saline. Fifty-two weeks after azoxymethane and saline treatment all the animals were necropsied, and colon and small intestinal tumor incidence (percentage of animals with tumors) and multiplicity (tumors/animal) were compared among various dietary groups. The results indicate that 40 and 80% MTD levels of dietary piroxicam and DFMO significantly (P less than 0.001) inhibited colon and small intestinal tumor incidence and multiplicity. DHEA analogue at 40% MTD level significantly decreased the small intestinal and colon tumor incidences (P less than 0.05), whereas 80% MTD of DHEA analogue inhibited only small intestinal tumor incidence. EA at 40 and 80% MTDs had no significant effect on colon tumor incidence (P greater than 0.05), but 80% MTD of EA showed a significant inhibitory effect on the incidence of small intestinal adenocarcinomas (P less than 0.01). In the combination study, 40 and 80% MTD levels of piroxicam plus DFMO significantly (P less than 0.001) inhibited colon adenocarcinoma incidence (8.3%) and multiplicity (0.08 +/- 0.04) (SE) when compared to colon adenocarcinoma incidence (72.2%) and multiplicity (1.14 +/- 0.18) in control diet-fed animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of different levels of calorie restriction on azoxymethane-induced colon carcinogenesis in male F344 rats.

Epidemiological and animal model studies indicate that increased calorie intake increases the risk for colon cancer development. Previous studies in animal models restricted the calorie intake severely, and none of these studies have investigated a dose-response effect of different levels of calorie restriction on colon carcinogenesis. The present study was designed to investigate the effect of various levels of calorie restriction on colon carcinogenesis in male F344 rats fed the low and high fat diets and the effect of these diets on the activities of colonic mucosal and tumor ornithine decarboxylase (ODC) and protein tyrosine kinase. Starting at 5 weeks of age, groups of male F344 rats were fed the low fat or high fat diets ad libitum. At 7 weeks of age, all animals except the vehicle-treated groups were given s.c. injections of azoxymethane (AOM) (15 mg/kg body weight, once weekly for 2 weeks). Four days after the second injection, groups of animals were restricted to 90, 80, or 70% of total calories consumed by the high fat ad libitum group (i.e., 10, 20, and 30% calorie restriction, respectively). In the low fat groups, animals were restricted to 80% of total calories consumed by the low fat ad libitum group (i.e., 20% restriction). Thirty-six weeks after AOM injections, all animals were necropsied and colon tumors were used for histopathology and ODC and protein tyrosine kinase analysis. In the second experiment, the protocol was the same as above except that the animals were sacrificed 5 days after the second AOM injection and colonic mucosal ODC and protein tyrosine kinase activities were assayed. The incidence and multiplicity of colon tumors were significantly inhibited in animals fed the high fat 20% calorie-restricted and high fat 30% calorie-restricted diets, as compared to those fed the high fat ad libitum diet. The regression coefficient representing the dose-response effect of different levels of calorie restriction in both high fat groups is significant. Results also indicate that AOM treatment significantly increased the colonic mucosal ODC and protein tyrosine kinase activities. This stimulation was inhibited by feeding the calorie-restricted diets. ODC and protein tyrosine kinase activities were lower in the colon tumors of animals fed the calorie-restricted diets.

Chemoprevention of colon carcinogenesis by concurrent administration of piroxicam, a nonsteroidal antiinflammatory drug with D,L-alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor, in diet.

The effect of three levels of piroxicam and three levels of D,L-alpha-difluoromethylornithine (DFMO) fed individually and in combination during the postinitiation phase of carcinogenesis was studied in male F344 rats to generate a data base on the efficacy and synergistic and additive effects of these compounds as inhibitors of colon carcinogenesis. The maximum tolerated dose of DFMO was determined in male F344 rats and found to be 5000 ppm in the AIN-76A diet. Piroxicam at levels of 25, 75, and 150 ppm and DFMO at concentrations of 400, 1000, and 4000 ppm (20, 50, and 80% maximum tolerated dose) in AIN-76 diet were tested individually and in combinations. At 7 weeks of age, while the rats were consuming the control diet (AIN-76A), all animals except the vehicle (saline)-treated controls were given a single s.c. injection of azoxymethane (CAS: 25843-45-2) at a dose level of 29.6 mg/kg body weight to induce intestinal tumors. One week after azoxymethane injection, animals were transferred to their respective experimental diets containing piroxicam and DFMO. Fifty-six weeks after azoxymethane injection, all animals were necropsied and colon and small intestinal tumor incidences and multiplicity were compared among the various dietary groups. Feeding of diets containing 75 and 150 ppm piroxicam or 1000 and 4000 ppm DFMO significantly inhibited the incidence (percentage of animals with tumors) of colon adenocarcinomas compared to that of control diet. The multiplicity (number of tumors/rat) of adenocarcinomas was significantly inhibited in animals fed the 25, 75, and 150 ppm piroxicam or 400, 1000, and 4000 ppm DFMO diets. Results analyzed by the linear regression method suggested a dose-dependent inhibition in colon adenocarcinoma incidence with increasing levels of piroxicam or DFMO. The incidence and multiplicity of colon adenocarcinomas were significantly inhibited in animals fed the diets containing combinations of 25, 75, and 150 ppm piroxicam and 400, 1000, and 4000 ppm DFMO. Piroxicam and DFMO administered together had a stronger inhibitory effect than did those given individually. Piroxicam and DFMO when administered individually had no significant inhibitory effect on colon adenoma incidence and multiplicity; in contrast, combinations of these compounds significantly inhibited colon adenomas. No consistent differences were found in the incidence and multiplicity of small intestinal tumors among the dietary groups.(ABSTRACT TRUNCATED AT 400 WORDS)

[A study of ornithine decarboxylase activity in tumor tissue and rectal mucosa in patients with colorectal cancer or adenoma].

Rectal mucosa from normal controls (n = 25) and tumor tissue and rectal mucosa from patients with colorectal cancer (n = 38) and adenoma (n = 35) were biopsied via colonoscopy. Ornithine decarboxylase (ODC) activity was determined in order to study the role of promoters in the process of colorectal carcinogenesis. ODC activity of cancer tissue was significantly higher than that of adenoma tissue. Normal mucosal ODC activity in rectum and sigmoid colon was 2 to 4 times higher than that in the proximal colon. Moreover, rectal mucosal ODC activity was significantly higher in patients with cancer or adenoma than that in normal controls. When ODC activity is regarded as an index of promoter, the possibility is suggested that cancer and adenoma developed in similar mucosa of the large bowel. Furthermore, ODC activity in colon cancer was significantly higher than that in rectal cancer. This suggests the possibility that TPA type promoter assumes a greater role in the process of carcinogenesis of colon cancer than that of rectal cancer.