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

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA

Michael J Graziano

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA

Edwin Goldenthal

MPI Research, Mattawan, Michigan 49071, USA

Alexander Gough

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA

Felix A de la Iglesia

Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA

1 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 pheny toin-induced lymphoma in mice and upon epidemiologic evidence of an association between anticonvulsive ther apy and lymphoma in epilepsy patients, the International Agency for Research on Cancer (IARC) has collectively regarded these data as limited evidence of carcinogeni city.

3 Two year carcinogenicity studies of standard bioassay design conducted in mice and rats yielded statistically significant increased incidence of hepatocellular adeno mas in mice at phenytoin plasma concentrations approx imating the therapeutic anticonvulsive range. Tumor incidence in rats was not affected. Previous carcinogeni city 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, hepatocel lular neoplasia in phenytoin-treated rodents appears to be of little significance to man.

Key Words: phenytoin • diphenylhydantoin • carcinogenicity • ro dent bioassays • human epidemiology

Human & Experimental Toxicology, Vol. 15, No. 4, 335-348 (1996)
DOI: 10.1177/096032719601500410


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