CHEMOPREVENTIVE EFFECT OF PERILLYL ALCOHOL ON 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE INDUCED TUMORIGENESIS IN (C3H HEJ-X-A/J)F-1 MOUSE LUNG/

This study was designed to test the chemopreventive potential of peril lyl alcohol, an inhibitor of farnesyltransferase, in a mouse lung tumo r bioassay. Perillyl alcohol is a naturally occurring monoterpene foun d in lavender, cherries, and mint. We have shown previously that the m ajority of lung tumors in this bioassay have an activating mutation in the K-ras gene, which occurs early in the development of mouse lung c arcinogenesis. The Ras protein undergoes a series of post-translationa l modifications, the first of which is farnesylation at the cysteine o f the C-terminal CAAX motif. These modifications lead to the anchoring of Ras p21 to the plasma membrane in its biologically active state. A ctivated Ras p21 couples growth regulatory signals from receptor tyros ine kinases to cytoplasmic second messengers. In a preliminary study, we determined the maximum tolerated dose of perillyl alcohol to be 75 mg/kg body weight. For the bioassay, 5-week-old male (C3H/He] X A/J) F 1 hybrid mice were randomized into trial groups, and treated with peri llyl alcohol three times per week i.p., starting 1 week prior to initi ation with the carcinogen NNK, and continuing for 22 weeks after initi ation. Our results show a 22% reduction in tumor incidence, and a 58% reduction in tumor multiplicity. Our study demonstrates that perillyl alcohol is an effective chemopreventive compound in the mouse lung tum or bioassay. (C) 1998 Wiley-Liss, Inc.