Tumorigenicity of cyclopenta[a]phenanthrene derivatives and micronucleus induction in mouse skin

The most potent carcinogen of the cyclopenta[a]phenanthrene series, 15, 16-dihydro-11-methylcyclopenta[a]phenanthren-17-one and its non-carcinogenic, unmethylated parent compound, were compared for their abilities to induce micronuclei in epidermal keratinocytes after application onto the dorsal skin of Skh/HR-1 hairless mice. Although both substances were shown to be mutagenic in vitro, only the 11-methyl derivative has been proven to initiate cancer in TO and Sencar mouse strains. In the present study, only the 11-methyl derivative was active as a cancer initiator in Skh/HR-1 mice. For studying micronucleus induction, a preliminary experiment was conducted to establish doses of both chemicals that allowed cell survival. Subsequently, micronucleus induction in epidermal keratinocytes was shown to agree with the cancer-initiating potential of the two compounds. Only the carcinogenic derivative induced a statistically significant increase in micronuclei, over the range 10-100 nmol. This is considerably lower than the dose of approximately 1600 nmol commonly used to initiate skin cancer in mice, but is comparable to the active dose range for skin micronucleus induction by benzo[a]pyrene, a chemical of equivalent carcinogenic potency.