BAY 12-9566N (BAY), which is a substituted 4-biarylbutyric
acid and has the properties of a
matrix metalloproteinase (
MMP) inhibitor, was tested in the accelerated
cancer bioassay (ACB). In the ACB, three different genotoxic
carcinogens were administered individually to groups of male and female Wistar rats, in initiation (IN) segments lasting 10 weeks, followed by BAY in promotion segments lasting 42 weeks, for a total of 52 weeks of treatment, followed by 12 weeks of recovery. The IN target organs in males were the liver using
diethylnitrosamine (DEN), and the lungs, using
N-nitrosodimethylamine (NDA), and in females, the mammary gland using
7,12-dimethylbenz(a)anthracene (DMBA). The study consisted of eight groups of 24 rats each as follows: controls (male and female), DEN alone (male), DEN/BAY (male), NDA (male), NDA/BAY (male), DMBA (female), and DMBA/BAY (female). The daily dose of BAY was 240 mg/kg in the diet, yielding a cumulative dose of 70,560 mg/kg. The cumulative doses of
carcinogens were 220 mg/kg DEN, 150 mg/kg NDA, or 15 mg/kg DMBA. No significant difference in
body-weight gain pattern was evident between any of the groups at 52 or 64 weeks. Rather, in males, DEN-induced
hepatocellular adenomas were reduced with BAY treatment from 29% to 21% (p < 0.05) and
carcinomas from 42% to 29% (p < 0.01). Also, in males, NDA-induced pulmonary
adenomas were reduced with BAY treatment from 38% to 21% (p < 0.01) and
carcinomas from 21% to 4% (p < 0.01). In females, DMBA-induced mammary gland
adenomas were reduced from 13% to 4% (p < 0.01) and
carcinomas from 54% to 42% (p < 0.05). Thus, BAY produced a consistent and significant reduction of
neoplasm development in both genders in three target tissues of carcinogenicity in which
neoplasms were induced by three different
DNA-reactive initiators. This inhibition may be due to inhibition of
MMP, leading to reduced neoplastic growth and development.