The studies presented were designed to test the efficacy of
farnesyltransferase inhibitors (FTIs) as potential chemopreventive compounds in the mouse lung
tumor model, and in tumor cell lines. The compounds included
manumycin,
gliotoxin, dihydroepiandrosterone (
DHEA),
perillyl alcohol (POH), and
FTI-276. Each of these compounds had the potential, based on in vitro and limited in vivo evidence, to inhibit mouse lung
tumorigenesis. In vitro studies were conducted with both K-ras-transformed NIH-3T3 cells and mouse lung
tumor epithelial cell lines. We utilized 2 primary mouse lung
tumor models that reliably produce lung
tumors with an oncogenic K-ras mutation when induded by
4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK).
Manumycin,
gliotoxin,
DHEA, and POH were administered 3 times per week peritoneally (i.p.), starting 1 week prior to
carcinogen treatment, and throughout the test period (4.5 months).
FTI-276 was delivered daily for 4 months by a time-release pellet method. Both the
manumycin and
gliotoxin treatment groups demonstrated 100% incidence and an increase in
tumor multiplicity over control, of 66% and 58% increase respectively (P < .05). Although
DHEA showed no significant chemopreventive effect, POH treatment demonstrated a 22% reduction in
tumor incidence (P < .05) and a 58% reduction in
tumor multiplicity (P < .05). Finally,
FTI-276 reduced both the
tumor multiplicity by 41.7% (P < .005), and the total
tumor volume/burden per mouse by 79.4% (P < .0001). The apoptotic index in FTI-276-treated
tumors showed an increase of 77% over control
tumors (P < .05). In vitro, all compounds demonstrated growth inhibition at a dose-response manner; however,
manumycin,
gliotoxin, and
DHEA demonstrated an initial increase in growth rate at lower doses. In summary, we have shown that POH and
FTI-276 are chemopreventive in a primary mouse lung
tumor model. In contrast,
DHEA was not significantly chemopreventive at the dosage utilized, and treatment of an immunocompetent host with
manumycin or
gliotoxin demonstrated a significant increase in tumorigenicity over
carcinogen control.