SENSITIVITY TO TUMOR PROMOTION OF SENCAR AND C57BL/6J MICE CORRELATES WITH OXIDATIVE EVENTS AND DNA DAMAGE

Significant differences in sensitivity to multistage carcinogenesis have been noted between mice that are sensitive (SENCAR) and resistant (C57BL/6j) to 12-0-tetradecanoyl-phorbol-13-acetate (TPA). However, the mechanism of this sensitivity has not yet been established. Recent studies from this laboratory have shown that TPA significantly enhances formation of hydrogen peroxide (H2O2) and oxidized DNA bases in SENCAR mouse skin, as it increases the infiltration of polymorphonuclear leukocytes (PMNs), as quantitated by myeloperoxidase (MPO). In the studies reported here, we compared SENCAR and C57BL/6J mice with respect to TPA-mediated edema, hyperplasia, PMN infiltration, oxidant formation and oxidative DNA damage in mouse skin. Topical application of two TPA doses (2 x 2 - 40 mug, 20 h apart) dose-dependently increased PMN infiltration and oxidant formation in both mouse strains, which was consistent with TPA-induced morphological alterations (edema and hyperplasia). However, at low TPA doses (2 - 4 mug), the increases over controls in the SENCAR mice were significantly greater (P < 0.01) than those in C57BL/6J mice. Comparison of the net values indicated that 4 mug TPA enhanced PMN infiltration (MPO units/cm2) and oxidant formation (nmol H2O2/cm2) in SENCAR mice by 7.7- and 11-fold respectively over those present in TPA-treated C57BL/6J mouse skin. At the same dose, TPA also significantly increased formation of thymidine glycol (dTG; 5.5-fold), 5-hydroxymethyl-2'-deoxyuridine (HMdU; 4.9-fold) and 8-hydroxyl-2-deoxyguanosine (8-OHdG; 11.4-fold) in SENCAR mouse epidermis. Then, the levels of all three declined. In C57BL/6J mice, there were virtually no increases at 4 mug TPA, but their levels gradually increased with higher TPA doses and reached maxima at 10 mug TPA for dTG (1.9-fold increase), at 20 mug TPA for 8-OHdG (6.0-fold), and at 30 mug TPA for HMdU (1.8-fold). We conclude that the TPA-mediated oxidative events and oxidative DNA modification by different doses of TPA correlate with the promoting potencies of those doses in both mouse strains. Therefore, they could be, at least in part, responsible for the strain-dependent sensitivity to tumor promotion.