Dc. Wolf et al., Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats, CARCINOGENE, 21(8), 2000, pp. 1553-1558
Induced cell proliferation is important in the mode of action of many non-g
enotoxic renal carcinogens. Since Tsc2 mutant (Eker) rats are genetically p
redisposed to the development of renal cell tumors, they provide a useful a
nimal model in which to study the action of renal carcinogens. Sodium barbi
tal was used as a model non-genotoxic renal carcinogen to test whether a co
ncentration that increased renal tubular proliferation without severe nephr
otoxicity would enhance tumor induction in a hereditary tumor model. First,
a subchronic concentration-response study was conducted in wild-type male
Long-Evans rats to determine increased cell proliferation without severe ne
phrotoxicity, Rats were dosed with sodium barbital in the feed at 0, 50, 25
0, 500, 1000, 2000 or 4000 p.p.m. for 3 or 8 weeks. Cell proliferation with
in the cortex and nephrotoxicity were quantitated, Enhanced proliferation w
ith minimal nephrotoxicity occurred at 500 p.p.m., A second study was condu
cted in male Tsc2 mutant rats given sodium barbital in the feed at 0, 100 o
r 500 p.p.m. from 9 weeks of age to either 6 or 12 months of age. An additi
onal group of rats was treated with sodium barbital for 6 months and then p
rovided control feed until 12 months of age, Rats necropsied at 6 months of
age had a concentration-dependent increase in preneoplastic and total rena
l lesions. Sodium barbital-treated rats necropsied at 12 months of age had
numbers of lesions that were not different from controls. Total combined pr
eneoplastic and neoplastic lesions in the 6 month, high dose group was the
same as the 12 month control group, These data show that sodium barbital ca
used progression to the stage of spontaneous renal lesions in Tsc2 mutant r
ats but did not increase their overall number. These data suggest that enha
nced cell proliferation without significant cytotoxicity exerted a promotio
nal influence in this hereditary model.