Loss of heterozygosity in (LewisxF344)F1 rat urinary bladder tumors induced with N-butyl-N-(4-hydroxybutyl)nitrosamine followed by dimethylarsinic acid or sodium L-ascorbate.
Dimethylarsinic acid (DMA), a main metabolite of arsenicals which are carcinogenic in man, exerts tumor-promoting activity on rat urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Sodium L-ascorbate (Na-AsA) is also a strong tumor promoter in this animal model. In this study, we used (LewisxF344)F, rats to compare molecular alterations in urinary bladder tumors caused by BBN followed by DMA or Na-AsA. Male, 6-week-old rats were given 0.05% BBN in their drinking water for 4 weeks, and then the rats in group 1 were maintained with no further treatment for 40 weeks. The animals of groups 2 and 3 were administered 0.01% DMA in their drinking water (group 2) or 5% Na-AsA in the powder diet (group 3) after the BBN treatment. Group 4 rats were given 0.05% BBN continuously for 36 weeks. At weeks 12, 20, 36 and 44, subgroups of rats were killed. Histopathological examination revealed promoting activity for DMA and, to a greater extent, Na-AsA on urinary bladder carcinogenesis. Loss of heterozygosity (LOH), detected with the polymerase chain reaction using 36 microsatellite markers, was found to be present in 2 of 9 (22%) urinary bladder tumors after treatment with DMA and 3 of 22 (14%) induced by continuous administration with BBN. No LOH was, however, detected in urinary bladder tumors after treatment with Na-AsA. The results thus suggest that the mechanisms of action of these two promoters, DMA and Na-AsA, may differ in rat urinary bladder carcinogenesis.
Chen
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Department of Pathology, Osaka City University Medical School, Osaka .
Na
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Wanibuchi
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Yamamoto
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Lee
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Fukushima
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D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D002085:Butylhydroxybutylnitrosamine; D002101:Cacodylic Acid / Q000494:pharmacology*; D015197:Carcinogenicity Tests; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D006965:Hyperplasia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
D002085:Butylhydroxybutylnitrosamine; D002101:Cacodylic Acid; D001205:Ascorbic Acid