Loss of Heterozygosity in (Lewis×F344)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 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 (Lewis×F344)F(1) 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.