Conversion from low grade to high grade of rat urinary bladder carcinomas.

The present study was conducted to test if low-grade carcinomas induced by a single dose of N-methyl-Nitrosourea (MNU) can be converted to high-grade carcinomas by a second identical dose of the carcinogen. The heterotopically transplanted rat urinary bladder system was used. Four wk after heterotopic bladder transplantation, the recipient male Fischer 344 rats were divided into 2 groups. The first group received 0.25 mg of MNU into heterotopically transplanted rat urinary bladder; the second group (controls) received 0.9% NaCl solution. At week 29 of the experiment, 1/3 of the animals from each group were killed for histological examination of the heterotopically transplanted rat urinary bladders. The remaining animals from each group were divided into 2 subgroups, the first receiving 0.25 mg MNU and the second, 0.9% NaCl solution. All animals were killed at 50 wk of the experiment. MNU-induced carcinomas at week 29 were all of low histological grade and were noninvasive. Longer follow-up without a second carcinogen administration resulted in both an increase in tumor incidence (P less than 0.005) and more tumors per bladder (P less than 0.001), but high-grade invasive carcinomas were rare. The second dose of MNU administered at the stage when low-grade carcinomas were prevalent (week 29) resulted in a significant increase in invasive high-grade carcinomas (P less than 0.01). Our data are consistent with the view that the second carcinogen administration induces a new mutation(s) within low-grade carcinomas which leads to invasive carcinomas.