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 embryonic zeta-globin promoter and develops cutaneous papillomas in response to specific chemicals, full thickness wounding, and ultraviolet radiation. Papilloma development in these mice has been suggested to be dependent upon activation of ras transgene expression, thus providing a potential model for studying ras-inhibitory compounds. Farnesyl transferase inhibitors (FTIs) prevent 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 administration of the tumor promoter TPA decreased tumor multiplicity compared to TPA-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 strain background or 50% C57BL/6. Histological examination of skin from Tg. AC(+/-):FVB/N mice revealed no differences with respect to 12-O-tetradecamoylpharbol-13-acetate (TPA)-mediated hyperplasia. Keratinocytes isolated from treated and control skin were assayed for ras transgene expression by reverse transcription-polymerase chain reaction, and expression was detected in both TPA- and FTI+TPA-treated tissue, although the appearance of transgene positive pre-papillomas was observed only in histological sections taken 21 d after the first treatment. In summary, we have used a regimen of topical application of an FTI (SCH 56582) to suppress TPA-mediated papillomagenesis in v-Ha-ras transgenic Tg.AC mice. These studies demonstrate that TPA-induced epidermal hyperplasia is a ras-independent process, while papilloma development in response to TPA treatment requires the function of activated ras.
Trempus
C S
CS
Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. trempus@niehs.nih.gov
Bishop
W R
WR
Njoroge
F G
FG
Doll
R J
RJ
Battalora
M S
MS
Mahler
J F
JF
Haseman
J K
JK
Tennant
R W
RW
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003433:Crosses, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005260:Female; D011905:Genes, ras; D005914:Globins / Q000235:genetics; D006720:Homozygote; D006965:Hyperplasia; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D011401:Promoter Regions, Genetic; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013997:Time Factors
D001552:Benzazepines; D004791:Enzyme Inhibitors; C121676:SCH 56582; D005914:Globins; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D013755:Tetradecanoylphorbol Acetate