Perspective on the carcinogenic potential of phenytoin based on rodent tumor bioassays and human epidemiological data

Phenytoin is a hydantoin-type anticonvulsive agent used extensively for nearly sixty years in the prophylactic treatment of grand mal and psychomotor seizures. 2. Based upon somewhat contentious evidence of phenytoin-induced lymphoma in mice and upon epidemiologic evidence of an association between anticonvulsive therapy and lymphoma in epilepsy patients, the International Agency for Research on Cancer (IARC) has collectively regarded these data as limited evidence of carcinogenicity. 3. Two year carcinogenicity studies of standard bioassay design conducted in mice and rats yielded statistically significant increased incidence of hepatocellular adenomas in mice at phenytoin plasma concentrations approximating the therapeutic anticonvulsive range. Tumor incidence in rats was not affected. Previous carcinogenicity studies have found similar increases in hepatic tumor incidence in mice. 4. Phenytoin is a known enzyme inducer and shows tumor promoting activity in chemically initiated mouse liver. Evidence for genotoxicity is weak or equivocal, consequently phenytoin-induced liver tumors appear to occur through nongenotoxic mechanisms. 5. Finally, despite six decades of extensive therapeutic use and thorough epidemiologic evaluation, there is no evidence for an association between liver cancer and phenytoin therapy in epilepsy patients. Thus, hepatocellular neoplasia in phenytoin-treated rodents appears to be of little significance to man.