A farnesyl transferase inhibitor suppresses TPA-mediated skin tumor development without altering hyperplasia in the ras transgenic Tg.AC mouse

The Tg.AC mouse carries an activated v-Ha-ras oncogene fused to an embryoni c zeta-globin promoter and develops cutaneous papillomas in response to spe cific chemicals, full thickness wounding, and ultraviolet radiation. Papill oma development in these mice has been suggested to be dependent upon activ ation of ras transgene expression, thus providing a potential model for stu dying ras-inhibitory componds. Farnesyl transferase inhibitors (FTIs) preve nt a critical posttranslational modification step necessary for activation of ras proteins. Our studies demonstrated that a tricyclic FTI (SCH 56582) applied directly to the skin of homozygous Tg.AC mice 1 h prior to administ ration of the tumor promoter TPA decreased tumor multiplicity compared to T PA-only controls. In addition, a reduction of TPA-induced tumor development was seen in similarly treated hemizygous Tg.AC mice either on an FVB/N str ain background or 50% C57BL/6. Histological examination of skin from Tg.AC( +/-) FVB/N mice revealed no differences with respect to 12-O-tetradecamoylp harbol-13-acetate (TPA)-mediated hyperplasia. Keratinocytes isolated from t reated and control skin were assayed for ras transgene expression by revers e transcription-polymerase chain reaction, and expression was detected in b oth TPA- and FTI + TPA-treated tissue, although the appearance of transgene positive pre-papillomas was observed only in histological sections taken 2 1 d after the first treatment. In summary, we have used a regimen of topica l application of an FTI (SCH 56582) to suppress TPA-mediated papillomagenes is in v-Ha-ras transgenic Tg.AC mice. These studies demonstrate that TPA-in duced epidermal hyperplasia is a ras-independent process, while papilloma d evelopment in response to TPA treatment requires the function of activated ras. (C) 2000 Wiley-Liss, Inc.