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PubMed1997

Morphological changes in the basement membrane during progression from non-invasive to invasive rat bladder cancer induced by N-butyl-N-(4-hydoxybutyl) nitrosamine.

OBJECTIVE: To investigate the ultrastructural changes in the basement membrane (BM) in the rat model of bladder cancer when progressing from non-invasive to invasive disease. MATERIALS AND METHODS: N-butyl-N-(4-hydoxybutyl) nitrosamine (BBN) was administered to 50 rats (7 weeks old) in their drinking water (0.05% BBN) for 28 weeks. At between 20 and 28 weeks, 10 rats were killed every 2 weeks and morphological changes of the BM were investigated by transmission electron microscopy and histological changes by light microscopy. RESULTS: At between 20 and 28 weeks, the transitional cell carcinoma (TCC) of the rat bladder induced by BBN progressed from non-invasive (stage Ta) to invasive (stage T1-2) disease. Focal thinning and discontinuity of the BM occurred in five of 26 rats with non-invasive TCC and in all 24 rats with invasive TCC. CONCLUSIONS: Stage Ta bladder cancer in the rat model may be associated with degradative changes in the BM and can be divided into two types, Ta1 where there is no degradation of the BM and Ta2, where the BM is degraded.

Animals↗
PubMed1999

Antitumour effects of the angiogenesis inhibitor AGM-1470 on rat urinary bladder tumours induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.

OBJECTIVE: To examine the antitumour effects of the angiogenesis inhibitor AGM-1470 (TNP-470) on rat urinary bladder tumours induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). MATERIALS AND METHODS: Fischer-344 rats were allocated to one of four groups of 15 rats each; in group 1, rats were administered AGM-1470 intraperitoneally, with group 2 acting as the control and given only saline; in group 3, AGM-1470 was instillation intravesically and group 4 acting as control (intravesical saline). All rats were given 0.05% BBN in their drinking water for 8 weeks and then given water with no BBN. AGM-1470 was administered at a dose of 30 mg/kg every other day for 6 weeks in group 1 and at 15 mg/kg once a week for 6 weeks in group 3. This treatment was commenced at 21 weeks after the start of BBN treatment, when tumorigenesis was apparent in all rat bladders; approximately 70-80% of the tumours were carcinomas. All rats were killed in the 27th week. The antitumour effects of AGM-1470 on the BBN-induced bladder tumours were evaluated macroscopically and histologically. The inhibitory effect of AGM-1470 on endothelial cell proliferation was assessed in groups 1 and 2 by immunohistochemical staining for Factor VIII-related antigen and by counting the microvessels. RESULTS: The number and volume of bladder tumours were significantly less in group 1 than group 2. In the latter, at least one bladder tumour developed in each of the 15 rats. Histologically, transitional cell carcinoma (TCC) was found in 13 rats and papilloma in two, with invasive cancer in three of the 13 TCCs. Bladder tumours developed in only four of the 15 rats in group 1. Carcinomas were found in three of these four rats and no invasive cancer was detected. The rats in group 1 had significantly fewer microvessels than the controls. The rats in group 4 also showed slightly but insignificantly less tumour growth and fewer carcinomas. In neither experiment were any major side-effects seen except for mild weight loss after AGM-1470 treatment. CONCLUSION: AGM-1470 inhibited the growth and malignant progression of BBN-induced bladder tumours in rats, apparently mainly by the inhibition of tumour vessel development. The intraperitoneal administration of AGM-1470 produced better results than did intravesical instillation. These results suggest that the angiogenesis inhibitor AGM-1470 is a promising agent for the treatment of human bladder cancer.

Animals↗
PubMed1981

Possible formation of nitrosamine in guinea pigs following exposure to nitrogen dioxide and dimethylamine.

The possibility of formation of nitrosamine was investigated in animals exposed to a combination of dimethylamine (DMA) and NO2. First, the distribution and covalent binding of DMA and dimethylnitrosamine (DMN) in rats and guinea pigs were determined. The apparent volume of distribution and biological half-life for [14C]-DMA or [14C]DMN did not reveal any species difference. In general, there were no marked differences in accumulation of radioactivity in tissues of guinea pigs and rats 4 h after the administration of DMA, while the guinea pig tissues showed higher accumulation after DMN administration. Nucleic acid fractions prepared from liver and lungs of both species following administration of DMN or DMA in vivo showed much higher covalent binding with DMN than with DMA. Furthermore, the covalent binding of DMN was found to be due to bioactivation, whereas the DMA binding was nonspecific. Since guinea pig liver showed a higher degree of covalent binding than rat liver, this species was used to investigate the possible increase in covalent binding in the presence of NO2 and DMA as a reflection of DMN formation. There was no evidence of enhancement of covalent binding when animals pretreated with [14C]-DMA were exposed for various lengths of time to different concentrations of NO2.

Animals↗
PubMed1989

Promotion by sodium barbital of renal cortical and transitional cell tumors, but not intestinal tumors, in F344 rats given methyl(acetoxymethyl)nitrosamine, and lack of effect of phenobarbital, amobarbital, or barbituric acid on development of either renal or intestinal tumors.

Comparative effects of four barbiturates, phenobarbital (PB), amobarbital (AB), sodium barbital (NaBB), and barbituric acid (BA) on the development of neoplasms in the intestinal tract and other organs were investigated in rats following initiation with methyl(acetoxymethyl)nitrosamine (DMN-OAc). Four-week-old F344/NCr male rats were given a single i.p. injection of 0.05 nmol DMN.OAc in 5 ml sterile phosphate buffered saline/kg body weight. Two weeks after DMN.OAc treatment, the animals were provided with either tap water or drinking water containing 500 p.p.m. of PB, NaBB, AB, or BA for the remaining experimental period. Control groups received a single i.p. injection of 5 ml of sterile phosphate buffer/kg body weight and 2 weeks later were given either tap water or drinking water containing 500 p.p.m. of one of the barbiturates listed above. Rats were killed at 52 weeks or 80 weeks after DMN.OAc injection. DMN.OAc induced multiple intestinal tumors that occurred mostly in the mucosa of the small intestine, especially the terminal ileum. None of the barbiturates had any effect on either incidence or multiplicity of intestinal tumors. PB significantly enhanced the development of hepatocellular tumors as well as thyroid follicular cell neoplasms in DMN.OAc initiated rats, while the subsequent administration of NaBB, but not other barbiturates, resulted in the development of renal cortical and pelvic transitional cell tumors. This is the first demonstration of promotion of carcinogenesis in renal pelvic transitional epithelium, a cell type not previously recognized as vulnerable to initiation by DMN.OAc given i.p. NaBB without prior administration of DMN.OAc induced severe nephropathy and focal hyperplasia of both renal cortical tubular and pelvic transitional cell epithelium. No such effects were observed with either PB, AB, or BA. Our results failed to confirm the earlier findings of others that intestinal epithelial carcinogenesis could be promoted by continuous oral administration of NaBB. However, these results strongly support and extend our previous conclusions that some barbiturates have broad organ specificities and promote epithelial carcinogenesis in more than one organ and tissue.

Adenoma↗
PubMed1990

H-ras activation and ras p21 expression in bladder tumors induced in F344/NCr rats by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Bladder tumors were induced in male F344/NCr rats by administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) at 500 p.p.m. in their drinking water for 12 weeks. Twenty-one bladder tumors that developed between 25 and 50 weeks after BBN administration was begun were evaluated for immunoreactivity with polyclonal or monoclonal antibodies raised against ras p21, for amplification of ras genes by Southern blotting, and for activating point mutations in ras genes by selective oligonucleotide hybridization of products from polymerase chain reaction (PCR). Increased expression of ras p21 was detected by avidin-biotin immunohistochemistry in 18/21 (85%) of the neoplastic bladder lesions. By Southern analysis, there was no significant amplification of H-ras, K-ras or N-ras in any of the tumors except one that showed a 5-fold amplification of K-ras. Point mutations in ras genes were detected by selective oligonucleotide hybridization of the products of PCR. Of the 21 bladder tumors, three tumors were shown to have mutations in codon 12 (GGA----GAA), six tumors in codon 61 (two CAA----CTA, four CAA----CGA), and one in both codon 12 (GGA----GAA) and codon 61 (CAA----CGA), all in H-ras. Thus 10 of 21 tumors has ras gene mutations in a portion of the tumor cells. The variable pattern of point mutation in H-ras suggests that these mutations may not all be a direct consequence of interaction of BBN metabolites with H-ras. Enhanced expression of ras p21 was always focal and was not necessarily associated with transforming ras mutations. It is therefore suggested that tumorigenesis in BBN-initiated bladder cells might involve H-ras activation as part of a multistep pathway; however, H-ras involvement is not obligatory for tumor development.

Animals↗
PubMed1991

Uracil-induced calculi and carcinogenesis in the urinary bladder of rats treated simultaneously with N-butyl-N-(4-hydroxybutyl)nitrosamine.

Urinary bladder carcinogenicity of uracil and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in combination was investigated in male F344 rats. Two experiments were performed: in the first animals were treated with 3.0, 1.0 and 0.3% uracil in the diet and/or 0.005% BBN in the drinking water for 36 weeks followed by a 4 week period without chemicals, the total observation time being 40 weeks; in the second rats received 3.0% uracil in the diet or 0.05% BBN in the drinking water for 4 weeks. In the first experiment, a markedly high incidence of carcinomas was observed in the urinary bladder with both 3.0% uracil alone (11/15, 73%) and 3.0% uracil plus 0.005% BBN (18/20, 90%) treatments. The multiplicity, i.e. numbers of carcinomas induced per 10 cm of basement membrane, was significantly higher with the latter treatment (P less than 0.05), as were proliferative lesions in the renal pelvis. Stone formation was observed in all 3.0% uracil treatment animals. In the second experiment, prostaglandin E2 levels in bladder tissue of uracil-treated animals proved to be significantly higher than in BBN-treated or untreated animals. Thus, the results clearly indicated that calculi associated with 3.0% uracil ingestion can themselves cause carcinoma development in the urinary bladder, while also acting as a potent co-carcinogen agent for BBN carcinogenesis.

Animals↗
PubMed1991

Direct DNA sequencing of the rat neu oncogene transmembrane domain reveals no mutation in urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide or N-methyl-N-nitrosourea.

Epidermal growth factor (EGF) and EGF-related growth factors are present in the urine, and EGF has been identified as a urinary component that enhances urinary bladder tumor formation in rats. Neu oncogene encodes a cell surface receptor similar to the EGF receptor and is known to be activated by a point mutation of DNA that encodes the transmembrane domain of the neu protein (p185). In this study, we examined the possible mutational activation of neu oncogene in 50 urinary bladder transitional cell carcinomas (TCC) induced in F344 rats by the following carcinogenesis models: (i) 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) (4 weeks)----3% uracil (20 weeks); (ii) 0.2% N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) (6 weeks)----5% sodium saccharin (72 weeks); and (iii) N-methyl-N-nitrosourea (MNU) 20 mg/kg body wt, i.p. twice per week for 4 weeks----3% uracil (20 weeks). The DNA sequence around the transmembrane domain of neu gene was amplified by PCR and sequenced. The results showed no mutation within the examined DNA sequences, indicating that neu oncogene is not activated by a point mutation in the transmembrane domain in urinary bladder carcinomas induced by BBN, FANFT or MNU.

Amino Acid Sequence↗
PubMed1992

Absence of ras oncogene activation in rat urinary bladder carcinomas induced by N-methyl-N-nitrosourea or N-butyl-N-(4-hydroxybutyl)nitrosamine.

Previously, we demonstrated point mutations of the H-ras gene in N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-induced rat urinary bladder carcinomas. In this study, ras oncogene activation was examined in urinary bladder carcinomas induced by N-(4-hydroxybutyl)nitrosamine (BBN) or N-methyl-N-nitrosourea (MNU) administration followed by uracil treatment. In the first experiment, MNU (20 mg/kg body wt) was i.p. injected into 11 male F344 rats twice a week for 4 weeks, followed by feeding 3% uracil for 20 weeks (MNU/uracil group). Ten rats were given only 3% uracil without MNU pretreatment. In the second experiment, 20 male F344 rats were given 0.05% BBN in the drinking water for 4 weeks, then fed 3% uracil for 20 weeks (BBN/uracil group). Another 20 rats were fed 3% uracil without the BBN pretreatment. Transitional cell carcinomas were induced in the urinary bladder of all rats in the MNU/uracil and BBN/uracil groups. Papillomas and hyperplasias were present in the rats given uracil without prior BBN or MNU. DNA and protein were extracted from the tumors (MNU/uracil or BBN/uracil groups) or from the scraped bladder epithelium (uracil alone groups). Sequences around codons 12, 13 and 61 of H-, K- and N-ras genes were examined by direct sequencing after polymerase chain reaction, and p21 was examined by Western blotting. No mutation was found within the examined sequences and p21 showed no changes in mobility. There was no difference in the level of p21 expression between rats treated with MNU/uracil or BBN/uracil compared to corresponding uracil alone groups. These results indicate that the ras oncogene was not activated in urinary bladder carcinomas induced by BBN or MNU in combination with uracil treatment, in contrast to previous findings with FANFT.

Animals↗
PubMed1994

p53 mutations in early neoplastic lesions of the urinary bladder in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

Rat experimental models using N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiating agent have been widely used to study carcinogenic processes in the urinary bladder. In this study, early neoplastic lesions from 10 male F344 rats treated with 0.05% BBN for 16 weeks were analyzed for changes in the H-ras or p53 genes by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing. Lesions were pooled for each of the 10 rats and six showed point mutations in the p53 gene and one in the H-ras gene. These results would indicate that BBN-induced rat urinary bladder carcinomas are similar to human urinary bladder carcinomas with respect to alterations in the p53 and H-ras genes and that p53 gene alterations are relatively early events in rat urinary bladder carcinogenesis induced by BBN treatment.

Animals↗
PubMed1994

DNA methylation adduct formation and H-ras gene mutations in progression of N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder tumors caused by a single exposure to N-methyl-N-nitrosourea.

After receiving 500 p.p.m. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water for an initial 10 weeks, rats were given a single i.p. injection of N-methyl-N-nitrosourea (MNU) at a dose of 50 mg/kg body wt at week 20 (at a stage when bladder tumor development had already occurred), and then maintained until they were killed at week 40. Three and six hours after the MNU injection, the DNA methylation adducts, O6-methyldeoxyguanine (O6-medG) and 7-methyldeoxyguanine (7-medG), were immunohistochemically revealed to be markedly more frequent in urothelial preneoplasias or neoplasias than in normal cells. These adducts were rapidly repaired, and although 7-dmeG in tumor cells still persisted after 72 h, they appeared essentially to have returned to normal levels. At the termination, conversion of transitional cell carcinomas (TCC) to squamous cell carcinomas (SCC) of the urinary bladder was significantly increased in the BBN+MNU group. The extent of invasion was also significantly greater with the additional MNU treatment. Expression of p21 protein, detected by immunohistochemistry, was comparable between the groups. Mutations in the H-ras gene were observed in one case each of the BBN and BBN+MNU groups, and both cases showed a G:C to A:T transition at codon 12. The present study thus suggested that while an additional single treatment with MNU of rats bearing BBN-induced bladder neoplasias is associated with significant, possibly mutation-dependent tumor progression, H-ras mutations are not necessary events.

Administration, Oral↗
PubMed1995

Frequent mutations of the p53 gene and infrequent H- and K-ras mutations in urinary bladder carcinomas of NON/Shi mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

To elucidate whether common genetic events in human urinary bladder carcinogenesis also occur in rodent models, we investigated the presence of p53, H- and K-ras mutations in 18 urinary bladder carcinomas induced by various concentrations of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male NON/Shi mice. Histopathologically, all were invasive, 11 being squamous cell carcinomas (SCCs) and the remaining seven being transitional cell carcinomas (TCCs). Using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis followed by DNA sequencing, p53, H- and K-ras mutations were observed in 14 (78%; exons 5-7), two (11%; one each on exons 1 and 2) and one (5.6%; exon 1) animals respectively. The frequencies of mutations in p53 exons 5, 6 and 7 were 7 (39%), 4 (22%), and 9 (50%) respectively, and no mutation was found in exon 8. All mutations involved one base-pair substitution with or without amino acid changes and the types of base-pair substitution were random. No evident association was observed between mutation sites and the histological phenotypes. In conclusion, p53 mutations are frequent in BBN-induced mouse invasive urinary bladder tumors, at similar levels to those observed for human high-grade invasive carcinomas, and this plus their distribution suggests their possible participation in this model of urinary bladder carcinogenesis.

Amino Acid Sequence↗
PubMed1995

Differences in cell proliferation and apoptosis between reversible and irreversible mucosal lesions associated with uracil-induced urolithiasis in N-butyl-N-(4-hydroxybutyl)nitrosamine-pretreated.

Differences between the reversible papillomatosis and preneoplastic lesions of the urinary bladder of rats were investigated in terms of cell proliferation and apoptosis after cessation of uracil administration. Animals were given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then uracil for 8 weeks in order to induce urinary bladder lesions. During this period and after cessation of treatment until week 20, subgroups of animals were killed to allow sequential assessment of cell kinetics and apoptosis. Labeling indices (LI) in papillomatosis showed a marked elevation after 2 weeks of uracil treatment with a rapid decline thereafter. In contrast, LI in dysplasias, papillomas and carcinomas gradually elevated during the uracil treatment. Cessation of the uracil stimulation resulted in a complete disappearance of labeled cells in areas of papillomatosis accompanied by significant appearance of apoptotic bodies in the epithelial cells and shrinkage of the lesions. In the focal dysplasias and papillomas, however, any reduction in LI was temporary and followed by a rapid reelevation. The number of apoptotic bodies were relatively few in neoplastic lesions. Thus, removal of growth-stimulating uracil-calculi resulted in return of hyperplastic epithelium to normal by a homeostatically controlled apoptotic mechanism. In contrast, preneoplasias and neoplasias demonstrated an autonomous growth ability.

Animals↗
PubMed1996

Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in rats.

Arsenicals are epidemiologically significant chemicals in relation to induction of urinary bladder cancer in man. In the present study, we investigated the dose-dependent promotion potential of dimethylarsinic acid (DMA), a major metabolite of inorganic arsenicals in mammals, for rat urinary bladder carcinogenesis. In experiment 1, 6-week-old male F344 rats were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then given one of several concentrations of DMA in their drinking water (groups 1-6: 0, 2, 10, 25, 50 and 100 p.p.m.) for 32 weeks. The development of preneoplastic lesions and tumors (papillomas and carcinomas) in the urinary bladder was enhanced by treatment with DMA in a dose-dependent manner. A significant increase in multiplicity of tumors (papillomas and carcinomas) was observed even at a low concentration of DMA (10 p.p.m.). On the other hand, no preneoplastic lesions and tumors were observed in the rats treated with DMA alone. In experiment 2, different concentrations of DMA (groups 1-4: 0, 10, 25 and 100 p.p.m.) in drinking water were administered to the rats for 8 weeks without prior initiation by BBN. A significant increase in the 5-bromo-2'-deoxyuridine labeling index and alteration of the surfaces of the urinary bladder epithelial cells, as revealed by scanning electron microscopy, provided evidence of a dose-dependent increase in cell proliferation due to the DMA treatment. These results suggest that DMA has the potential to promote rat urinary bladder carcinogenesis and one of the mechanisms involved is its stimulation of cell proliferation in the urinary bladder epithelium.

Animals↗
PubMed1997

Genetic instability and p53 mutations in metastatic foci of mouse urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

In a variety of human malignancies, alteration of the p53 tumour suppressor gene is known as a significant indicator of late progression events including invasion and metastasis, with a possible close relationship to genetic instability. Mutational analysis of the p53 and H-ras genes was performed for 10 pairs of N-butyl-N-(4-hydroxybutyl)nitrosamine-induced invasive mouse urinary bladder carcinomas and metastatic foci. p53 Mutations were found in nine of 10 (90%) primary carcinomas and seven of 10 (70%) metastatic foci. A total of eight p53 mutations in primary carcinomas were common in metastatic foci in six pairs. Additional p53 or H-ras mutations which were not identified in the primary carcinomas were found in three metastatic foci. Evaluation of the allelic distribution of the p53 mutations using RT-PCR, PCR and subcloning, further indicated possible intra-tumour genomic heterogeneity or excess copy numbers of the p53 gene due to genetic instability. Overall, p53 alterations were frequent in mouse urinary bladder carcinomas demonstrating progression. The results suggest that genetic instability might underlie generation of additional genetic alterations in this animal model.

Animals↗
PubMed1997

High incidence of nitrosamine-induced tumorigenesis in mice lacking DNA repair methyltransferase.

The enzyme O6-methylguanine-DNA methyltransferase repairs alkylation-induced DNA damage, O6-methylguanine and O4-methylthymine, the former being formed more frequently. Previously, by means of gene targeting, we generated mice in which alleles for methyltransferase were disrupted. We now use these mouse lines, which are totally deficient in methyltransferase activity, to examine protective effects of the enzyme against tumor formation. In gene-targeted female mice given an i.p. injection of 5 mg/kg of dimethylnitrosamine, a larger number of liver and lung tumors occurred, as compared with normal female mice treated in the same manner. In male mice given a lower dose of carcinogen, the difference between normal and gene-targeted mice was statistically insignificant although more tumors did form in the gene-targeted mice. Methyltransferase apparently afforded protection from nitrosamine-induced tumorigenesis.

Animals↗
PubMed1998

The dynamics of the imprinted H19 gene expression in the mouse model of bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The imprinted H19 gene product is an oncofetal RNA molecule in humans. It is expressed in fetal bladder, down-regulated postnatally and is re-expressed in human bladder carcinoma. This study was designed to investigate the dynamics of the expression of H19 in the mouse bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and its relation to stages of neoplastic transformation. BBN was administered to mice in the drinking water for 26-28 weeks. The bladders were removed at 5-10 week intervals for histopathological examination and for in situ hybridization for H19 RNA, using a 35S-labeled probe. Following BBN administration expression of H19 first appeared after 5 weeks in the lamina propria adjacent to the basement membrane, concomitant with mucosal hyperplasia. At 11 weeks focal expression was noted in epithelial cells. Invasive carcinomas, of the transitional and squamous sub-types, were seen after 20 weeks and more of BBN administration. At this stage H19 expression was observed in scattered tumor cells, in the connective tissue stroma of the tumor and in the lamina propria underlying the remaining hyperplastic/dysplastic mucosa. Abundant expression of H19 was evident in fetal bladder but was absent in normal adult bladder. We conclude that, similar to humans, the H19 gene product is an oncofetal RNA molecule in the experimental mouse model of bladder carcinoma. In this model H19 is expressed in the connective tissue of the lamina propria prior to its expression in epithelial cells, concurrent with preneoplastic changes in the transitional epithelium of the bladder.

Animals↗
PubMed1998

Clonal analysis of urothelial carcinomas in C3H/HeN<-->BALB/c chimeric mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The histological background for multifocal and metachronous development of urothelial carcinomas remains equivocal, although accumulated genetic evidence suggests monoclonal origin of multiple urothelial carcinomas. Clonal development of various preneoplastic and neoplastic urothelial lesions of C3H<-->BALB/c chimeric mice induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was immunohistochemically investigated using a C3H strain-specific antibody. All tumor masses induced in the mice treated with 0.05% BBN for 20 weeks were composed of neoplastic cells of a single parental type, which is indicative of monoclonal lesions. Three of 10 animals harbored two or more separate carcinomas of different clonal type, which is indicative of multicentric development applicable in this model. Using DNAs derived from urothelial carcinomas and tumor-adjacent urothelium of chimeric mice, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing were performed for p53 gene exons 5-7. p53 mutations were identified in four of 11 (36%) dysplasias and non-invasive carcinomas (carcinoma in situ and pTa tumor) and 13 of 22 (59%) invasive carcinomas. Only in a single case were identical p53 mutations found in separate urinary bladder carcinomas. In contrast to the random distribution of urothelial proliferating units in chimeric mice without chemical supplement, invasive carcinomas in BBN-treated mice were accompanied by widely-distributed preneoplastic and neoplastic lesions of the same clonality, which occasionally had frequent foci of microinvasion. This is indicative of lateral clonal expansion of the clones, which precedes the bulk of invasive carcinomas. Thus, two aspects of 'field change' of the urothelium became evident in this model: either independent transformation events or lateral clonal expansion might, respectively, result in multicentric and monoclonal carcinoma development in the urinary tract.

Animals↗
PubMed1981

The cellular DNA content and profile of dimethyl nitrosamine induced marine lung tumors in relation to their histopathology.

A total of 61 lung tumors induced in NMRI mice by the carcinogen dimethyl nitrosamine were classified as solid adenomas or papillary tumors. Single cell suspensions from each of these tumors were analyzed by flow cytometry according to DNA content. The adenomas contained stemlines having a diploid DNA content, a finding which is in accordance with the benign nature of these tumors. In the papillary tumors heteroploid stemlines were often found in addition to diploid cells, this seems to be a sign of their malignant properties. The significance of the heteroploidy and the clustering of stemlines at the near diploid and the tetraploid levels in these tumors is discussed.

Animals↗