Loss of heterozygosity in (LewisxF344)F-1 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 carci nogenic in man, exerts tumor-promoting activity on rat urinary bladder carc inogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), Sodi um L-ascorbate (Na-AsA) is also a strong tumor promoter in this animal mode l. In this study, we used (LewisxF344)F-1 rats to compare molecular alterat ions in urinary bladder tumors caused big BBN followed by DMA or Na-AsA, Ma le, 6-week-old rats were given 0.05% BBN In their drinking water for 4 week s, and then the rats in group 1 were maintained with no Further treatment f or 40 weeks, The animals of groups 2 and 3 were administered 0.01% DMA in t heir drinking water (group 2) or 5% Na-AsA in the powder diet (group 3) aft er the BEN 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. Histopat hological 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 m arkers, was found to be present in 2 of 9 (22%) urinary bladder tumors afte r treatment with DMA and 3 of 22 (14%) induced by continuous administration with BBN, No LOH was, however, detected in urinary bladder tumors after tr eatment 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.