Chemopreventive efficacy of promising farnesyltransferase inhibitors.
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.
Lantry
L E
LE
Department of Pathology and Surgery, Medical College of Ohio, Toledo, Ohio, USA.
Zhang
Z
Z
Crist
K A
KA
Wang
Y
Y
Hara
M
M
Zeeck
A
A
Lubet
R A
RA
You
M
M
D016475:3T3 Cells; D000236:Adenoma / Q000139:chemically induced / Q000737:chemistry / Q000473:pathology / Q000517:prevention & control*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis; D018890:Chemoprevention; D004273:DNA, Neoplasm / Q000032:analysis; D003687:Dehydroepiandrosterone / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D019084:Fluorescent Antibody Technique, Indirect; D005912:Gliotoxin / Q000627:therapeutic use; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000139:chemically induced / Q000737:chemistry / Q000473:pathology / Q000517:prevention & control*; D008715:Methionine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D039821:Monoterpenes; D011090:Polyenes / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D053284:Polyunsaturated Alkamides; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D013729:Terpenes / Q000627:therapeutic use
D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; C404062:FTI 276; D039821:Monoterpenes; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D018809:Proliferating Cell Nuclear Antigen; D013729:Terpenes; C032208:perillyl alcohol; D003687:Dehydroepiandrosterone; D005912:Gliotoxin; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C054474:manumycin