Multiple stages in radiation carcinogenesis of rat skin.

Epithelial cell cancers are induced in rat skin by ionizing radiation in a manner that is consistent with the dual action (i.e., two alterations) hypothesis of radiation effects on DNA. This hypothesis states simply that two initial alterations, presumably in the DNA, are necessary to start a normal cell on the pathway to cancer. The initial radiation-induced alteration in the DNA is repairable as indicated by the reduction in tumor incidence with increasing time between dose fractions; the repair halftime is estimated to be 3.0 +/- 1.0 hr. Theoretical predictions of a specific dependence of tumor incidence on linear energy transfer (LET) have been verified experimentally for two specific LET values. However, the theoretical formulation provides no guidance regarding the observed reduction in the carcinogenic action of radiation with age at the time of exposure. Analysis of the tumor DNA for oncogene activation indicated k-ras and c-myc oncogenes were activated in highly anaplastic rat skin cancers, whereas only one of these oncogenes, usually c-myc, was activated in comparatively benign basal cell carcinomas and in squamous cell carcinomas.