Chemopreventive efficacy of promising farnesyltransferase inhibitors

Citation
Le. Lantry et al., Chemopreventive efficacy of promising farnesyltransferase inhibitors, EXP LUNG R, 26(8), 2000, pp. 773-790
Citations number
39
Language
INGLESE
art.tipo
Article
Categorie Soggetti
da verificare
Journal title
EXPERIMENTAL LUNG RESEARCH
ISSN journal
0190-2148 → ACNP
Volume
26
Issue
8
Year of publication
2000
Pages
773 - 790
Database
ISI
SICI code
0190-2148(200012)26:8<773:CEOPFI>2.0.ZU;2-3
Abstract
The studies presented were designed to test the efficacy of farnesyltransfe rase 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 limit ed in vivo evidence, to inhibit mouse lung tumorigenesis. In vitro studies were conducted with both K-ras-transformed NIH-3T3 cells and mouse lung tum or epithelial cell lines. We utilized 2 primary mouse lung tumor models tha t reliably produce lung tumors with an oncogenic K-ras mutation when induce d by 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK). Manumycin, glio toxin, DHEA, and POH were administered 3 times per week peritoneally (IP), starting 1 week prior to carcinogen treatment, and throughout the test peri od (4.5 months). FTI-276 was delivered daily for 4 months by a time-release pellet method. Both the manumycin and gliotoxin treatment groups demonstra ted 100% incidence and an increase in tumor multiplicity over control, of 6 6% and 58% increase respectively (P < .05). Although DHEA showed no signifi cant chemopreventive effect, POH treatment demonstrated a 22% reduction in tumor incidence (P < .05) and a 58% reduction in tumor multiplicity (P < .0 5). 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 ap optotic index in FTI-276-treated tumors showed an increase of 77% over cont rol tumors (P < .05). In vitro, all compounds demonstrated growth inhibitio n at a dose-response manner; however, manumycin, gliotoxin, and DHEA demons trated an initial increase in growth rate at lower doses. In summary, we ha ve shown that POH and FTI-276 are chemopreventive in a primary mouse lung t umor 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 carcin ogen control.