Sensitivity of Subpopulations of Mouse Skin Papillomas to Malignant Conversion by Urethane or 4-Nitroquinoline /V-Oxide

Papillomas induced in SENCAR mice by initiation with 7,12-dimethylbenz(a)anthracene and promotion by treatment for 10-12 weeks with 12-O-tetradecanoylphorbol-13-acetate (TPA) convert to malignancy at a low frequency. The rate of malignant conversion can be increased by either (a) promoting with TPA for a shorter duration or (h) treatment of papilloma-bearing mice with certain genotoxic chemicals, such as 4nitroquinoline A'-oxide (4-NQO) or urethane. The spontaneous conver sion rate of papillomas promoted by 5 weeks of TPA exposure is severalfold higher than that of papillomas arising later during TPA promotion. Here, we compared the sensitivity to the converting agents 4NQO and urethane of papillomas promoted by TPA for either 5, 10, or 20 weeks. In the mice promoted for 5 weeks with TPA, the already high spontaneous conversion frequency was increased 2.5 times by 4-NQO. A 2-fold increase was found after 10 weeks of TPA promotion. In contrast, no increase was seen with 4-NQO exposure begun after 20 weeks of TPA promotion. Similar results were found with urethane as converting agent. The sensitivity of the papillomas induced by short-term TPA treatment to induced conversion remains high even after a 16-week period without TPA treatment; when urethane exposure was delayed until week 21 after TPA promotion for weeks 1-5, a 2.4-fold increase in the conversion frequency was observed.