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M Tatematsu

Publications and source records attributed to M Tatematsu.

At least 37 records · Page 2Linked to original sources
PubMed2001

A vitamin D analog ameliorates glomerular injury on rat glomerulonephritis.

OCT (22-oxa-calcitriol), a vitamin D analog, has been reported to show strong inhibitory effects on mesangial cell proliferation in vitro. In the present study, we report a study of the effect of OCT on anti-thy-1 glomerulonephritis. Both OCT and 1,25(OH)(2)D(3) significantly inhibited mesangial cell proliferation, the degree of glomerulosclerosis, and albuminuria at day 8 compared to the disease control group. The OCT-treated group showed normal calcium levels but the 1,25(OH)(2)D(3)-treated group showed higher levels. The disease control group showed a marked increase of type I and type IV collagens, and alpha-smooth muscle actin (alpha-SMA) compared to the normal group. The treatment of OCT or 1,25(OH)(2)D(3) significantly reduced the expression of these proteins. The mRNA of the glomeruli of anti-thy-1 model expressed significantly higher levels of type I and type IV collagens, and alpha-SMA at day 8 compared to normal rats. Treatment with OCT or 1,25(OH)(2)D(3) inhibited the mRNA expressions of type I and type IV collagens, as well as that of alpha-SMA. These data demonstrate that OCT inhibits mesangial cell proliferation and extracellular matrix expansion with a low calcemic activity. Disease control rats showed significantly increased levels of transforming growth factor-beta1 protein in the glomeruli, but treatment with OCT or 1,25(OH)(2)D(3) markedly reduced this expression. The levels of mRNA in glomeruli were also consistent with these protein levels. Therefore, the suppressive effect of OCT may be mediated by inhibition of transforming growth factor-beta1. The present results suggest that OCT has potential for use in therapeutic strategy for the treatment of glomerulonephritis without inducing hypercalcemia.

Actins↗
PubMed2001

Late phase responses after nasal challenges with allergen and histamine in asthmatic children with perennial nasal allergy.

OBJECTIVE: Late phase response (LPR) is difficult to investigate in patients with perennial nasal allergy because of their continuous presentation with nasal symptoms. Contribution of histamine to the LPR is also controversial. In this study, we investigated whether exogenous histamine can induce LPR in asthmatic patients with perennial nasal allergy to house dust. METHODS: A total of 40 asthmatic children were divided into clinical, subclinical and non-rhinitis groups based on their daily nasal symptoms. Changes in nasal patency and in inflammatory cells in nasal secretion were quantitatively measured for 6 h by acoustic rhinometry and light microscopy respectively before and after nasal challenge with allergen or histamine. RESULTS: The allergen challenge produced a significant biphasic decrease in nasal patency in the subclinical group and a marginal decrease in the clinical group, with increases in eosinophils 6 h after the challenge. By contrast, histamine challenge induced significant responses in the clinical group and only a slight response in the subclinical group. Eosinophils also accumulated in nasal secretion of the clinical group to significant levels 6 h after histamine challenge. Eosinophil accumulation following histamine challenge was earlier than that after exposure to allergen. CONCLUSION: We conclude that LPR can be demonstrated in asthmatic children with perennial nasal allergy. Exposure to exogenous histamine also induced LPR, mediated mainly by eosinophil-related mediators.

Adolescent↗
PubMed2001

Role of N-methyl-N-nitrosourea in the induction of intestinal metaplasia and gastric adenocarcinoma in Mongolian gerbils infected with Helicobacter pylori.

BACKGROUND: Progression from intestinal metaplasia to neoplasia has not been demonstrated experimentally. The hypothesis that gastric adenocarcinoma arises from intestinal metaplasia was tested in a Mongolian gerbil model of Helicobacter pylori (H. pylori) infection. METHODS: One hundred and fourteen specific pathogen-free gerbils were divided in five groups. A and D: infected with H. pylori and administered the carcinogen N-methyl-N-nitrosourea (MNU); C and E: received MNU; B: H. pylori, but no MNU. Animals were killed at 41 weeks, stomachs were mapped, and the relationship between metaplasia and cancer was assessed. RESULTS: Intestinal metaplasia occurred more frequently in the H. pylori-infected, MNU-treated gerbils than in those receiving H. pylori inoculation only (P < 0.01). Carcinomas arose only in H. pylori-infected animals receiving MNU (8 well differentiated, 2 poorly differentiated, and 10 signet ring). Intestinal metaplasia occurred more frequently in association with intestinal-type carcinoma. CONCLUSIONS: Intestinal metaplasia and adenocarcinoma arise in stomachs subjected to the same injuries (in this study, H. pylori and MNU). Only two intestinal-type carcinomas were contiguous to intestinal metaplasia; all other tumors developed most commonly at non-metaplastic sites. This suggests that in this animal model H. pylori and MNU induce several phenotypes of gastric cancer, but intestinal metaplasia may be a direct precursor only in a subset of the intestinal-type tumors.

Adenocarcinoma↗
PubMed2001

Decreases of metallothionein and aminopeptidase N in renal cancer tissues.

Good molecular markers for investigating the biochemical differences between renal cancer and surrounding tissues have not yet been developed. Sixteen kidney samples (clear cell RCC) were investigated to determine the differences in the protein components between renal cancer and surrounding tissues, using HPLC analysis. The metallothionein (MT) and zinc levels were consistently lower in renal cancer tissues compared with in surrounding tissues. The mean concentration of MT in normal tissues surrounding renal tumors was about 15 times higher than that in cancer tissues. An immunohistochemical study confirmed that the expression of MT in renal cancer tissues was lower than that in adjacent normal tissues. The activities of aminopeptidases (APs) were significantly decreased in renal cancer tissues compared with in adjacent normal tissues. An immunohistochemical study and Western blot analysis confirmed that the expression of AP-N in renal cancer tissues was also lower than in adjacent normal tissues. These results suggest that the immunohistochemical detection of MT and AP-N could provide useful information as a pathological diagnostic tool for classifying renal cancer and surrounding tissues.

Biomarkers, Tumor↗
PubMed2001

Differential effects of partial hepatectomy and carbon tetrachloride administration on induction of liver cell foci in a model for detection of initiation activity.

Differential effects of partial hepatectomy (PH) and carbon tetrachloride (CCl(4)) administration on induction of glutathione S-transferase placental form (GST-P)-positive foci were investigated in a model for detection of initiation activity. Firstly, we surveyed cell proliferation kinetics and fluctuation in cytochrome P450 (CYP) mRNA levels by means of relative-quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and CYP 2E1 apoprotein amount by immunoblotting (experiment I) after PH or CCl(4) administration. Next, to assess the interrelationships among cell proliferation, fluctuation of CYPs after PH or CCl(4) administration and induction of liver cell foci, the non-hepatocarcinogen, 1,2-dimethylhydrazine (DMH) was administered to 7-week-old male F344 rats and initiated populations were selected using the resistant hepatocyte model (experiment II). In experiment I, the values of all CYP isozyme mRNAs after PH or CCl(4) administration were drastically decreased at the 12-h time point. From 72 h, mRNAs for all CYP isozymes began increasing, with complete recovery after 7 days. The CYP 2E1 apoprotein content in the PH group fluctuated weakly, whereas in the CCl(4) group it had decreased rapidly after 12 h and was still low at the 48 h point. In experiment II, induction of GST-P-positive foci was related to cell kinetics in the PH group, with about a 6-h time lag between time for carcinogen administration giving greatest induction of GST-P-positive foci and peaks in bromodeoxyuridine (BrdU) labeling, presumably due to the necessity for bioactivation of DMH. With CCl(4) administration, induction of foci appeared dependent on the recovery of CYP 2E1. In conclusion, PH was able to induce cell proliferation with maintenance of CYP 2E1, therefore being advantageous for induction of liver cell foci in models to detect initiation activity.

Animals↗
PubMed2001

Hexosaminidase-altered aberrant crypts, carrying decreased hexosaminidase alpha and beta subunit mRNAs, in colon of 1,2-dimethylhydrazine-treated rats.

Aberrant crypt foci (ACF), consisting of morphologically irregular crypts, are thought to be precancerous lesions for colon cancers. For their molecular analysis, it is necessary to avoid contamination with adjacent normal crypts and stromal cells. Decreased hexosaminidase activity in ACF, which has been histochemically demonstrated, was used in the present study to classify isolated crypts in combination with morphological changes. The length, rim diameter, and width (average SD, microm) of hexosaminidase-positive (Hex + ) crypts were 238.6 +/- 40.4, 89.5 +/- 22.9, and 57.6 +/- 14.0, respectively. For hexosaminidase-negative (Hex - ) crypts, the values were 314.4 +/- 77.8, 140.3 +/- 45.7, and 97.3 +/- 34.7, the width being 1.69 times greater (P < 0.0001). Crypts wider than 115 microm (approximately 2 times the average size of Hex + crypts) were all from ACF, judging from hexosaminidase staining. To analyze transcription levels of Hex alpha and beta subunits (Hexa and Hexb, respectively), real-time relative quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed using the LightCycler system. In aberrant crypts, both Hexa and Hexb were significantly down-regulated to 0.266 (P < 0.002) and 0.131 (P < 0.001) units, respectively, compared with those in morphologically normal crypts, with beta-actin as the internal standard. This decrease could be a molecular marker for precancerous enzyme-altered ACF.

1,2-Dimethylhydrazine↗
PubMed2001

Sequential histopathological changes in vivo after suicide gene therapy of gastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats.

Gastrointestinal cancer is the most important clinical target of gene therapy. Suicide gene therapy, such as with the herpes simplex virus type 1 thymidine kinase (HSV-TK) gene, has been shown to exert antitumor efficacy in various cancer models in vitro. We previously reported in situ gene transfer and gene therapy for gastric cancer induced by N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in dogs. Here, we describe the sequential histopathological changes after suicide gene therapy of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer in rats. Gastric tumors were induced by MNNG in 38 / 73 (52%) of Wistar strain rats. The suicide gene therapy group (14 rats) was subjected to in situ gene transfer with a recombinant adenovirus vector carrying the HSV-TK gene driven by CAG promoter (Ad.CAGHSV-TK) in gastric tumor, followed by the antiviral drug ganciclovir (GCV). To observe the histopathological changes at various times after HSV-TK / GCV gene therapy, groups of animals were sacrificed at 3, 8, and 30 days after gene transfer. Apoptosis in the gastric tumors was detected by the TUNEL method to assess the efficacy of HSV-TK / GCV gene therapy, and it was marked in the 8- and 30-day treatment groups compared to the sham operation controls (P < 0.001). Various histopathological changes, degeneration of cancer tissue and fibrosis after necrosis and apoptosis were significantly greater in the 30-day treatment group. The HSV-TK gene was detectable in peripheral blood by PCR until 30 days after gene transfer. These results may be useful in devising a method of suicide gene therapy for humans.

Adenoviridae↗
PubMed2001

[The role of Helicobacter pylori infection and effect of eradication in experimental animal models of gastric carcinogenesis].

Helicobacter pylori (Hp) was concluded to be 'a definite carcinogen' by WHO/IARC in 1994. We have demonstrated that Hp infection enhances chemical carcinogen-induced stomach carcinogenesis in Mongolian gerbils (MGs) using N-methyl-N'-nitro-N-nitrosoguanidine or N-methyl-N-nitrosourea. Not only well-differentiated but also poorly differentiated and signet ring cell types of cancers are observed, mimicking the human case. Eradication of Hp was found to be effective of preventing enhancing effects. Hp infection alone, without chemical carcinogens, caused submucosal proliferating lesions, but not gastric carcinomas, in contrast to reports that Hp infection alone may act on a complete carcinogen. Precise pathological assessment is required to solve this controversy. Here we demonstrate alleviation of Hp induced gastric lesions with eradication in MGs.

Animals↗
PubMed2001

[Rapid quantitative detection of free cancer cells in the peritoneal cavity of gastric cancer patients with real-time RT-PCR, and its prognostic significance].

We have established a rapid and quantitative detection method using real-time RT-PCR on the LightCycler instrument. This method can reproducibly quantitate 10-10(5) CEA expressing colon carcinoma cells per 10(7) peripheral blood leukocytes, a sensitivity comparable with conventional RT-PCR with a wide linear measuring range. Analysis of peritoneal washes from 241 gastric cancer patients with this assay revealed relative values of CEA transcripts that correlate well with the depth of tumor invasion. The sensitivity and specificity of real-time RT-PCR with a cut-off value of 0.25 were 88% and 81%, respectively. At this cut-off value, patients in the real-time RT-PCR (+) group were found to suffer from peritoneal metastasis with a high frequency, while peritoneal recurrence was very rare among patients with real-time RT-PCR (-) results. These results indicate a positive correlation between CEA mRNA levels in peritoneal washes and patient prognosis. We conclude that real-time RT-PCR with hybridization probes is a sensitive, quantitative, specific and rapid method to detect free cancer cells in peritoneal washes.

Ascitic Fluid↗
PubMed2001

Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibody.

Helicobacter pylori attach to the gastric mucosa with adhesin, which binds to Lewis b (Le(b)) or H type I carbohydrate structures. The Secretor (Se) gene and Lewis (Le) gene are involved in type I Le antigen synthesis. The present study was performed to investigate the possibility that Se and Le gene polymorphisms alter the risk of H. pylori infection. Two hundred thirty-nine participants were genotyped for Se and Le and tested for the presence of anti-H. pylori IgG antibodies. Using the normal gastric mucosa from 60 gastric cancer patients, we assessed immunohistochemically whether type I Le antigen expression depended on the Se and Le genotypes. The H. pylori infection rate was positively associated with the number of Se alleles (se/se group, 45.1%; Se/se group, 64.6%; and Se/Se group, 73.3%) and negatively associated with the number of Le alleles (le/le group, 76.4%; Le/le group, 68.3%; and Le/Le group, 55.6%). When the subjects were classified into three groups [low risk, (se/se, Le/Le) genotype; high risk, (Se/Se, le/le), (Se/Se, Le/le), and (Se/se, le/le) genotypes; moderate risk, other than low- or high-risk group], the odds ratio relative to the low-risk group was 3.30 (95% confidence interval, 1.40-7.78) for the moderate-risk group and 10.33 (95% confidence interval, 3.16-33.8) for the high-risk group. Immunohistochemical analysis supported the finding that Se and Le genotypes affected the expression of H. pylori adhesin ligands. We conclude that Se and Le genotypes affect susceptibility to H. pylori infection.

Adult↗
PubMed2001

Real time reverse transcriptase polymerase chain reaction of urinary cytokeratin 20 detects transitional cell carcinoma cells.

PURPOSE: We evaluate the diagnostic use of cytokeratin 20 messenger (m) RNA quantitation in urine as a marker of urothelial transitional cell carcinoma using the real time reverse transcriptase polymerase chain reaction (RT-PCR). MATERIALS AND METHODS: Spontaneously voided urine was obtained from 47 patients with urothelial transitional cell carcinoma (carcinoma group), 19 other urological diseases (noncarcinoma group) and 27 healthy volunteers (control group). Quantification of cytokeratin 20 was performed with mRNA extracted from urine samples with primers and hybridization probes specific for cytokeratin 20 on a LightCycler instrument (Roche Diagnostics Corp., Indianapolis, Indiana). RESULTS: This method allowed reproducible quantitation of 10 to 106 cytokeratin 20 expressing colon carcinoma cells per 107 peripheral blood leukocytes, comparable to the sensitivity of conventional RT-PCR with a wide linear measuring range. Cytokeratin 20 mRNA values in the carcinoma group (mean 35,850) were significantly higher than noncarcinoma (171) and control groups (4.55, p <0.0001 and <0.0001, respectively). Urinary cytokeratin 20 mRNA values significantly correlated with tumor grade, urinary cytological class, immunostaining pattern and depth of tumor invasion. Sensitivity and specificity of real time RT-PCR with a cutoff value of 15 were 81% and 83%, whereas those of conventional cytology were 28% and 100%, respectively. CONCLUSIONS: These results indicate that real time cytokeratin 20 RT-PCR is a sensitive, quantitative, rapid and specific method to detect free cancer cells in the urine, with good potential for monitoring recurrence of urothelial transitional cell carcinoma.

Adult↗
PubMed2000

Timing of N-methyl-N-nitrosourea administration affects gastric carcinogenesis in Mongolian gerbils infected with Helicobacter pylori.

In Mongolian gerbils, the gastric mucosa shows dramatic changes after Helicobacter pylori inoculation. The influence of the timing of N-methyl-N-nitrosourea (MNU) administration after H. pylori inoculation on gastric carcinogenesis was investigated. Ninety-two gerbils were divided into four groups. One group was given MNU at 24 weeks, and another at 1 week, after H. pylori inoculation. The other groups received only MNU. Stomachs were excised for histological examination 20 weeks after completing the MNU treatment. Carcinomas arose only in animals given MNU 1 week after H. pylori inoculation. In the relationship between H. pylori and gastric carcinogenesis, H. pylori is a promoter rather than an initiator, and other environmental factors (the timing of MNU administration) play important roles.

Adenocarcinoma↗
PubMed2000

Rapid quantitative detection of carcinoembryonic antigen-expressing free tumor cells in the peritoneal cavity of gastric-cancer patients with real-time RT-PCR on the lightcycler.

Detection of free cancer cells in the peritoneal cavity by RT-PCR using carcinoembryonic antigen (CEA) as a target gene is a more sensitive predictor of peritoneal dissemination than conventional cytology in gastric-cancer patients. Difficulties with this method are the lack of quantitative assessment of free cancer cells and the length of time before completion. To overcome these problems, we have established a rapid and quantitative detection method using a novel real-time fluorescence PCR system (LightCycler). Using this device with hybridization probes as fluorophores, we detected CEA mRNA in peritoneal washes during surgery (within 3 hr) without any post-PCR procedure. This method could reproducibly quantitate 10 to 10(6) CEA-expressing colon carcinoma cells per 10(7) peripheral blood leukocytes, a comparable sensitivity to conventional RT-PCR with a wide dynamic range. Analysis of peritoneal washes from 109 gastric-cancer patients with this assay revealed relative values of CEA transcripts that correlated well with the depth of tumor invasion (p < 0.01). Average values of CEA transcript in peritoneal washes in patients with cytology (-)/RT-PCR(-), cytology (-)/RT-PCR(+) and cytology (+)/RT-PCR(+) results were 0.64, 1,525 and 6,715, respectively. Moreover, CEA transcripts in peritoneal washes in patients with synchronous peritoneal metastasis were more than 50-fold higher than in those without metastasis. These results suggest a positive correlation between CEA mRNA levels in peritoneal washes and prognosis. We conclude that real-time RT-PCR with hybridization probes is a sensitive, quantitative, specific and rapid method to detect free cancer cells in peritoneal washes. This clinically relevant system is a powerful technique to evaluate the risk of peritoneal recurrence in patients with gastric cancer.

Carcinoembryonic Antigen↗
PubMed2000

Eradication diminishes enhancing effects of Helicobacter pylori infection on glandular stomach carcinogenesis in Mongolian gerbils.

To investigate the nature of the link between Helicobacter pylori (Hp) infection and stomach carcinogenesis, a study of the glandular stomach of Mongolian gerbils (MGs) was performed. MGs were treated with N-methyl-N-nitrosourea (MNU), followed by inoculation with Hp (groups 1 and 2) or without Hp (group 3), or infected with Hp (groups 4 and 5) or inoculation without Hp (group 6) followed by MNU administration. At week 21, the animals in groups 2 and 5 underwent an eradication procedure. At week 50, the incidences of adenocarcinomas in group 1 (15 of 23) and group 4 (9 of 26) were significantly higher than in group 3 (1 of 15) and group 6 (1 of 18), respectively. Moreover, those in group 2 (5 of 24) and group 5 (2 of 22) were lower than in groups 1 and 4, respectively. This study shows that Hp eradication may be useful as a prevention approach against stomach cancer.

Adenocarcinoma↗
PubMed2000

Chromosomal mapping of genes controlling development, histological grade, depth of invasion, and size of rat stomach carcinomas.

Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are widely used as a model of differentiated-type human stomach cancers. ACI/N (ACT) rats are susceptible and BUF/Nac (BUF) rats are resistant to MNNG-induced stomach carcinogenesis, and the presence of an autosomal gene with a dominant BUF allele has been suggested. In this study, we performed a carcinogenicity test by giving MNNG in drinking water to 117 male ACI x (ACIxBUF)F1 backcross rats. Each of 100 effective rats was diagnosed for its "carcinoma development" and when it was bearing stomach carcinoma(s), for histological grade, depth of invasion, and size and number of tumors. Carcinoma development was diagnosed based both on the age of the rat and on the presence of stomach carcinoma(s). Linkage analysis was performed with the genotypes of 161 loci, covering 1637 cM of the rat genome. Contrary to our original expectations, the most influential gene was the one on chromosome (chr.) 15, Gastric cancer susceptibility gene 1 (Gcs1), which confers susceptibility to stomach carcinogenesis (LOD, 3.8) with a dominant BUF allele by promoting conversion from adenomas to carcinomas. Two resistance genes on chr. 4 and chr. 3, Gastric cancer resistance gene 1 (Gcr1) and Gcr2, were shown to confer dominant resistance (LOD, 2.7 and 2.6, respectively). Gcs1, Gcr1, and Gcr2 exerted additive effects on the development of stomach carcinomas. A gene on chr. 16, Gcr3, was indicated to reduce the depth of invasion (LOD, 2.2) and sizes of tumors (LOD, 1.9). No linkage was obtained using the number of tumors. These findings show that the coordinate effect of a susceptibility gene, Gcs1, and two resistance genes, Gcr1 and Gcr2, is responsible for the development of MNNG-induced stomach carcinomas and that Gcr3 is responsible for the growth of a stomach carcinoma, reflected in the depth of invasion and in the tumor size.

Animals↗
PubMed2000

Summation of initiation activities of low doses of the non-hepatocarcinogen 1,2-dimethylhydrazine in the liver after carbon tetrachloride administration.

Summation of initiation by low doses of the indirect-acting non-hepatocarcinogen, 1,2-dimethylhydrazine (DMH) after proliferative stimulation with a necrogenic dose of carbon tetrachloride (CCl4) was investigated in terms of the induction of glutathione S-transferase placental form (GST-P) positive liver cell foci. Cell kinetics of liver after CCl4 i.g. treatment were examined with bromodeoxyuridine (BrdU) labeling (experiment I). To assess the correlation between cell proliferation and induction of liver cell foci, DMH (10 mg/kg i.g.) was administrated to 7-week-old male F344 rats at 12, 24, 36, 48, 60, 96 h after CCl4 i.g. and initiated populations expanded using the resistant hepatocyte model (experiment IIA). Subsequently, effects of repeated administration (10 mg/kg, four times, i.g.) of DMH were compared with the results of a single administration (40 mg/ kg, i.g.) with the same total dose (experiment IIB). In experiments I and IIA, the numbers and areas of GST-P-positive foci increased with the BrdU labeling index at the time of DMH treatment (maximum after 60 h). In experiment HB, repeated exposure of DMH at 10 mg/kg, four times resulted in significant (P<0.05) increase in number and area of GST-P-positive foci compared with the single administration (40 mg/kg). Thus, multiple low dose treatments during cell proliferation might be most effective for detection of weak initiation activity.

1,2-Dimethylhydrazine↗
PubMed2000

Effect of intragastric application of N-methylnitrosourea in p53 knockout mice.

Nullizygous p53 knockout (p53(-/-)) mice are highly susceptible to spontaneous tumorigenesis, in particular malignant lymphomas at an early age. Heterozygous p53 knockout (p53(+/-)) mice develop spontaneous tumors less frequently but may show increased susceptibility to chemical carcinogens. In this study, p53(-/-), p53(+/-), and p53 wild-type (p53(+/+)) mice were treated with N-methylnitrosourea (MNU) by gastric intubation (5 microg/g body weight) three times per week for 5 wk, starting at 5-6 wk of age. The surviving mice were killed when they were 56-57 wk old. All eight p53(-/-) mice treated with MNU developed malignant lymphomas with a shorter latent period (mean age = 16.4+/-0.5 wk) than their spontaneous tumors (61%, at age 23.3+/-1.4 wk). In p53(+/-) mice treated with MNU, malignant lymphomas developed at a higher frequency (eight of 27, 30%) than did spontaneous lymphomas (5%). Development of sarcomas in p53(-/-) and p53(+/-) mice was also significantly enhanced by treatment with MNU. All eight thymic lymphomas and three sarcomas in the p53(+/-) mice showed a loss of the remaining wild-type p53 allele. These results indicate that intragastric MNU treatment significantly enhanced spontaneous development of malignant lymphomas and sarcomas in both p53(-/-) and p53(+/-) mice. In the stomachs of 12 p53(+/-) mice, that were killed at the end of the experiment, two adenomas, one carcinoma in situ, and four adenocarcinomas were observed. In the stomachs of 31 p53(+/+) mice, eight adenomas and one carcinoma in situ were detected. The overall incidence of tumorous changes in the stomachs of p53(+/-) (seven of 12, 58%) and p53(+/+) (nine of 31, 29%) mice were not significantly different (P = 0.090). However, adenocarcinomas invading the submucosa were observed in p53(+/-) mice (four of 12, 33%) but not in p53(+/+) mice (zero of 31; P = 0. 004), suggesting a slightly higher susceptibility to gastric carcinogenesis induced by MNU in p53(+/-) mice. Mol. Carcinog. 28:97-101, 2000.

Adenocarcinoma↗