TUMOR-PROMOTING ACTIVITY OF 2,4-DINITROFLUOROBENZENE

The aim of this study was to determine whether the skin-sensitizing ag ent 2,4-dinitrofiuorobenzene (DNFB) would elicit the same morphologica l and biochemical events that are characteristic of 12-O-tetradecanoyl phorbol-13-acetate (TPA). While single applications of 0.1% or 0.2% DN FB produced only mild epidermal hyperplasia, multiple applications pro duced pronounced hyperplasia, Compared with TPA, a single application of DNFB produced small increases in ODC activity, although a second DN FB treatment produced a greater response. Both DNFB and TPA caused mar ked induction of ODC, c-fos and c-jun mRNA. Vascular permeability incr eased significantly in response to DNFB, such that after 15 hr the res ponse was quantitatively the same as for TPA. Repeated TPA produced th e same response as a single application, but repeated DNFB resulted in a response that was half that of TPA. In contrast to TPA, DNFB failed to activate partially purified protein kinase C (PKC), although it di d cause transient down-regulation of activity 15 hr after treatment. T he ability of DNFB to induce ODC activity, however, was unaffected by prior down-regulation of PKC. DNFB was also shown to promote tumors in initiated SSIN mice. Twice-weekly applications of 0.1% or 0.2% DNFB r esulted in approximately 65% and 85% of the mice developing an average of 2.0 or 3.2 tumors each, respectively. These results demonstrate th at DNFB elicits many of the same changes as TPA and that it does so in a PKC-independent manner. (C) 1995 Wiley-Liss, Inc.