Codon 61 Mutations in the c‐Harvey‐ras Gene in Mouse Skin Tumors Induced by 7,12‐Dimethylbenz[a]anthracene Plus Okadaic Acid Class Tumor Promoters

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Abstract
Three okadaic acid class tumor promoters, okadaic acid, dinophysistoxin‐1, and calyculin A, have potent tumor‐promoting activity in two‐stage carcinogenesis experiments on mouse skin. DNA isolated from tumors induced by 7,12‐dimethylbenz[a]anthracene (DMBA) and each of these tumor promoters revealed the same mutation at the second nucleotide of codon 61 (CAA → CTA) in the c‐Ha‐ras gene, determined by the polymerase chain reaction procedure and DNA sequencing. Three potent 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐type tumor promoters, TPA, teleocidin, and aplysiatoxin, showed the same effects. These results provide strong evidence that this mutation in the c‐Ha‐ras gene is due to a direct effect of DMBA rather than a selective effect of specific tumor promoters.