Biomedical subjects

Keiichirou Morimura

Publications and source records attributed to Keiichirou Morimura.

64 records · Page 4Linked to original sources

PubMed2002

Effect of ethanol treatment on metabolic activation and detoxification of esophagus carcinogenic N-nitrosamines in rat liver.

In order to elucidate the mechanism underlying enhancement by ethanol of N-nitrosodiethylamine (DEN)- and N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in rats, hepatic levels of cytochrome P-450 (CYP) enzymes, mutagenic activation of several N-nitrosamines and three kinds of UDP-glucuronyltransferase (UDPGT) activities were assayed in F344 rats. Immunoblot analyses of microsomal CYP proteins revealed induction of CYP2E1 (approximately 2-fold), but not CYP2B1/2, 1A1/2 or 3A2, by treatment with 10% ethanol in the drinking water for 2 weeks. In contrast, s.c. treatment with 0.5 mg/kg NMBA three times per week for 2 weeks produced no significant alterations in the levels of these CYP species. Ethanol treatment also elevated the mutagenic activities of N-nitrosodimethylamine (DMN), DEN and N-nitrosopyrrolidine (NPYR) in strain TA100 up to 2.1-, 1.6- and 2.3-fold above each control, respectively. However, this was not the cases for four N-nitrosamines, including NMBA, in strain TA100 and two heterocyclic amines and aflatoxin B(1) in strain TA98. In addition, ethanol did not affect UDPGT activities towards 4-nitrophenol, bilirubin and testosterone. Hepatic CYP species responsible for mutagenic activation of selected N-nitrosodialkylamines were confirmed by use of specific CYP inducers and inhibitors with the liver from F344 and Wistar rats, indicating that DMN, DEN and NMBA are selectively activated by CYP2E1, predominantly by CYP2E1 with a slight contribution by CYP2B2 and selectively by CYP2B1/2, respectively. These results demonstrate that ethanol exerts an enhancing effect on mutagenic activation by CYP2E1 of DMN, DEN and NPYR, but does not affect that of NMBA and the other carcinogens by CYP2B1/2, 1A1/2 and 3A2 and UDPGT1A1, 1A6 and 2B1 activities. Consequently, this suggests that enhancement by ethanol of DEN-induced esophageal carcinogenesis in F344 rats can be attributed to an increase in hepatic activation during the initiation phase, but that of NMBA-induced tumorigenesis is not attributable to metabolic activation and inactivation via glucuronidation in liver.

Animals↗

PubMed2002

Lack of a dose-response relationship for carcinogenicity in the rat liver with low doses of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline or N-nitrosodiethylamine.

For a long period, it has been generally considered that carcinogens, particularly genotoxic ones, have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged with regard to assessment of cancer risk to humans. Here we show that a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, forms DNA adducts at low doses, but does not induce glutathione S-transferase placental form (GST-P)-positive foci (considered to be preneoplastic lesions) or 8-hydroxy-2'-deoxyguanosine in rat liver. Moreover a N-nitroso compound, N-nitrosodiethylamine, at low doses was also found not to induce GST-P-positive foci in rat liver. These results imply that there is a no-observed effect level for hepatocarcinogenesis by these genotoxic carcinogens.

Animals↗

PubMed2002

p53 null mutations detected by a p53 yeast functional assay predict a poor outcome in young esophageal carcinoma patients.

Esophageal carcinoma is one of the most common gastrointestinal malignant neoplasms in the world. Recent advances in treatment modalities as well as surgical resection techniques have improved the changes of survival of patients with esophageal carcinoma, although the prognosis is worse than for the other gastrointestinal carcinomas. A more precise stratification beyond clinicopathological classification may help determine optimal treatment. The importance of p53 gene mutations in the pathogenesis of human esophageal carcinoma is well established, but it is still controversial whether the presence of p53 mutations adversely affects individual patient prognosis. In this study, we investigated the p53 mutations of esophageal carcinomas and their correlation with clinicopathologic factors. We employed a p53 yeast functional assay because it is highly sensitive and can detect mutations based on the actual function of the p53 gene, clarifying more precisely the role of this gene in esophageal carcinomas. We also studied young patients (< or =65 years old), because our previous study raised the possibility of differences in the importances in esophageal carcinogenesis in young and old patients. Of 43 young esophageal carcinoma patients (42 squamous cell and 1 undifferentiated carcinoma), 38 (88.4%) harbored p53 mutations. Twenty-seven missense and 11 null mutations were detected, but the presence of p53 mutations did not correlate with any clinicopathologic factor. However, the null mutation was a significant indicator of a poor outcome (P=0.0278). All except one patient who harbored null mutation died within 3 years after a macroscopically curative resection. These data suggest that the type of p53 gene mutation may be predictive of outcome in young esophageal carcinoma patients. Furthermore, null mutations causing loss of function of the gene product may play a more important role than missense mutations in tumor progression.

Aged↗

PubMedDate not supplied

Value of GST-P positive preneoplastic hepatic foci in dose-response studies of hepatocarcinogenesis: evidence for practical thresholds with both genotoxic and nongenotoxic carcinogens. A review of recent work.

Recent low-dose carcinogenesis studies, including major group projects are reviewed. The prevailing paradigm is that carcinogens, particularly genotoxic compounds, have no threshold in exerting their potential for cancer induction. However, the nonthreshold hypothesis can be challenged for cancer risk assessment in humans. A recent very large-scale cooperative effort in Japan furthermore showed that the genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, forms DNA adducts and 8-hydroxy-2'-deoxyguanosine at low doses, but does not induce glutathione S-transferase placental form (GST-P) positive foci as preneoplastic lesions in rat liver (< or = 10 ppm in diet). Moreover, very low doses of a N-nitroso compound. diethylnitrosamine (DEN), were also found not to significantly induce GST-P positive foci in rat liver (< or = 0.01 ppm in drinking water). Given the direct correlation between induction of the preneoplastic lesions in the short-term and carcinomas in the longer term with different carcinogens, the results imply a practical nonobserved effect level for hepatocarcinogenicity. Similar results were also observed with so-called nongenotoxic carcinogens such as phenobarbital (PB) and p,p-dichlorodiphenyltrichloroethane (DDT), which do not exert positive effects on lesion development at very low doses. Furthermore, experiments with application of PB and DDT after treatment with DEN indicate that at very low doses (< or = 2 ppm in diet), they may even inhibit the development of GST-P positive foci. The data reviewed provide evidence that preneoplastic foci in the liver can be employed as end-point lesions in place of tumors and that exposure to very low levels of carcinogens, typical of those found in the human environment, does not necessarily present as a risk factor.

Animals↗

PubMedDate not supplied

Weak enhancing effects of simultaneous ethanol administration on chemically induced rat esophageal tumorigenesis.

Excessive alcohol consumption is associated epidemiologically with an elevated risk of esophageal cancer. In this study, we examined the effects of simultaneous administration of ethanol on N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. Groups 1-3 were treated with NMBA at a dose of 0.5 mg/kg body weight (high dose), and groups 4-6 received a dose of 0.1 mg/kg body weight (low dose), by s.c.-injection, 3 times per week for the first 5 weeks. Groups 1 and 4 were given ethanol free water as controls. Groups 2 and 5 were treated with 10% ethanol in their drinking water only at the time of NMBA treatment, while groups 3 and 6 were administrated the supplement continuously up to the end of the experiment. Macroscopically, with high dose NMBA-initiation, simultaneous 5-week and continuous 24-week ethanol administration demonstrated a tendency to increase the incidence and multiplicity of tumors, and also microscopically the multiplicity of papillary hyperplasias. In low dose groups, the incidence of esophageal papillary hyperplasias was significantly increased by continuous 24-week ethanol administration. Immunohistochemistry, proliferating cell nuclear antigen (PCNA) positive indices tended to be increased in tumors by simultaneous 5-week and continuous 24-week ethanol administration, but cyclin D1 expression was not affected. These data suggest that simultaneous ethanol administration have weak enhancing effects, and also promoting effects in post-initiation phase is present on NMBA-induced rat tumorigenesis.

Alcohol Drinking↗

PubMedDate not supplied

Clinicopathologic and immunohistochemical features of surgically resected small cell carcinoma of the esophagus.

Esophageal small cell carcinoma (SmC) is considered an aggressive cancer carrying a poor prognosis, although the rarity of this tumor has impeded statistical evaluation. We reviewed records of 457 esophageal cancer patients treated in our department from 1986 to 2000, comparing clinicopathologic factors and post-treatment outcomes, for 9 patients with SmC, most undergoing esophagectomy including lymphadenectomy, with data from 128 patients with esophageal squamous cell carcinoma (SqC) invading to the muscular layer or beyond. Immunohistochemical features were compared between the SmC and 12 consecutive SqC. All patients studied had localized disease according to preoperative staging. SmC showed more ulcerative and infiltrative growth, and more aggressive lymphatic spread, than SqC. All SmC patients had lymph node metastasis (thoracic nodes, 9 patients: abdominal 6; cervical 1). All SmC specimens but no SqC were immunoreactive for neuron-specific enolase. Two and three SmC specimens were reactive for epithelial membrane antigen and keratin, respectively. Survival of SmC patients after esophagectomy (median, 11 months) was worse than for SqC patients (p=0.013). However, 1 SmC patient remains alive at 76 months. Survival was not related to any clinicopathologic or immunohistochemical features. While SmC shows aggressive behavior and worse outcomes than SqC, combining esophagectomy with chemotherapy or radiotherapy may prolong survival.

Aged↗

PubMedDate not supplied

No inhibition of urinary bladder carcinogenesis in rats with intravesical instillation of alpha-galactosylceramide.

The immunostimulatory a-galactosylceramide, KRN 7000 ((2S,3S,4R)-1-O-(a-D-galactopyranosyl)-2-(N-hexacosnoylamino)-1,3,4-octadecatrienol), may be anticipated to have antitumor activity in vivo apart from any direct toxicity to cancer cells. In this experiment, inhibition of rat bladder carcinogenesis by intravesically instillated KRN7000 was investigated. Male Fischer 344 rats, 6-weeks-old at the start, were divided into 4 groups, all first receiving the carcinogen, 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine, in their drinking water for 12 weeks. Then groups 1 and 2 respectively were administered 500 and 50 mg/kg of KRN7000 intravesically once weekly for 17 weeks. Group 3 similarly received only 0.3 micro/l of saline (vehicle control). Group 4 did not undergo bladder catheterization. On macroscopic examination at 30 weeks, multiplicities and sizes of bladder tumors in the KRN 7000 high and low-dose groups were not significantly different from those of the vehicle control group. Histologic examination confirmed no significant variation in incidences of carcinomas or preneoplastic lesions in the bladder among groups 1 to 4. Thus the results indicate that intravesical instillation of KRN7000 does not inhibit bladder carcinogenesis in rats.

Adjuvants, Immunologic↗

PubMedDate not supplied

Lack of preventive efficacy of FK228, a histone deacetylase inhibitor, against N-butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder carcinogenesis in p53+/- and p53+/+ mice.

BACKGROUND: The efficacy of FK228, a histone deacetylase inhibitor that is currently under early clinical trials for cancer therapy, against N-butyl-N-(4-hydroxybutyl)- nitrosamine (BBN) -induced mouse urinary bladder carcinogenesis was examined. MATERIALS AND METHODS: Heterozygous p53-deficient (p53+/-) and wild-type (p53+/+) mice were given FK228 (0, 0.01 and 0.1 mg/kg i.p., 3 times/week, respectively) after 10 weeks of 0.05% BBN treatment, and were sacrificed at 22 and 24 weeks after the start, respectively. RESULTS: There was no significant difference in the incidence of urinary bladder tumors among groups in the p53+/- or p53+/+ mice, although the high dose of FK228 increased the p21WAF1 mRNA expression in urinary bladder cancers in animals of both genotypes. CONCLUSION: The present data indicate a lack of any inhibitory effects of FK228 on BBN-induced mouse urinary bladder carcinogenesis under the present conditions.

Animals↗

PubMedDate not supplied

Inhibition of rat urinary bladder carcinogenesis by the antiangiogenic drug TNP-470.

Potential inhibitory effects of the antiangiogenic drug TNP-470 on rat urinary bladder carcinogenesis were investigated in F344 male rats initiated with 0.05% BBN in the drinking water for 8 weeks. Group 1 was then continuously treated with TNP-470 by subcutaneous injection using osmotic minipump until the end of the experiment; group 2 served as the control with only initiation. The incidences and multiplicities of papillomas and carcinomas in the TNP-470-treated group were significantly decreased compared to the control group values along with the tumor vascular density. In conclusion, TNP-470 can inhibit rat urinary bladder carcinogenesis, presumably through its effects on angiogenesis.

Angiogenesis Inhibitors↗

PubMedDate not supplied

Lack of promoting effects of phenobarbital at low dose on diethylnitrosamine-induced hepatocarcinogenesis in TGF-alpha transgenic mice.

Phenobarbital (PB), a rodent non-genotoxic carcinogen, showed hormesis, biphasic effects on rat liver carcinogenesis. To test the hypothesis that the hormesis earlier observed for PB induced hepatocarcinogenesis might also exist in the TGF-alpha transgenic mice model, one which is highly susceptible to carcinogenesis, the carcinogenic or promotion effects of a wide range of phenobarbital (PB) concentrations were investigated. Two weeks after a single i.p. dose of 5 mg /kg bw of diethylnitrosamine (DEN) to 15 day old mice, animals were treated with diet containing PB at doses of 0, 2, 15 or 500 ppm. The incidence and multiplicity of tumors, including hepatocellular adenomas and carcinomas, were significantly increased by the high dose of PB, but no significant difference among the groups receiving 2 and 15 ppm for liver tumors when compared to DEN alone group. The proliferating cell nuclear antigen indices for liver tumors and surrounding hepatocytes in high dose PB treated mice were significantly increased, but no change was noted at the lower doses. The total cytochrome P450 content in the liver was also elevated by 500 ppm of PB, while hepatic 8-OHdG levels demonstrated no significant change. In conclusion, PB at high dose enhances DEN-induced hepatocarcinogenesis in TGF-alpha transgenic mice, but low doses lack any significant effects. One possible mechanism of phenobarbital carcinogenicity might be influenced by cytochrome P450 system exhibiting a strong promoting activity for liver of mice.

Animals↗