Abstract
Though humans are continually exposed to various environmental carcinogens, the mechanism of combined carcinogenesis has been only deduced from oncogenic actions of individual agents. Here, we analyzed experimental mammary carcinogenesis caused by a combination of radiation and a chemical carcinogen, 1-methyl-1-nitrosourea (MNU). Seven-week-old female Sprague-Dawley rats were treated either with gamma-rays (2 Gy), MNU (40 mg/kg, i.p.), or a combination of gamma-rays and MNU (gamma/MNU). Rats were sacrificed by 50 weeks of age to collect tumors for histological and mutational analyses. The gamma/MNU treatment induced adenocarcinomas, but not fibroadenomas, more efficiently than gamma-rays or MNU alone. The H-ras mutation was not frequent in radiation-induced carcinomas, and was characteristic to MNU-induced carcinomas in individually treated groups. In the gamma/MNU group, H-ras-mutated, but not non-mutated, tumors were induced more efficiently than in the MNU-treated group. These results indicate that the combined exposure to radiation and a chemical carcinogen elicits an unexpected cooperativity in which pre-irradiation enhances chemical carcinogenesis predominantly through the mechanism involving H-ras mutation.
