THE CHEMOPREVENTION OF CANCER BY MEVALONATE-DERIVED CONSTITUENTS OF FRUITS AND VEGETABLES

Anutritive isoprenoid constituents of fruits, vegetables, cereal grain s and essential oils exhibit a spectrum of anticarcinogenic activities . The induction of hepatic Phase II detoxifying activities by dietary isoprenoids appears to underlie their blocking action. The second anti carcinogenic action of the dietary isoprenoids, suppression of the gro wth of chemically initiated and transplanted tumors is; we suggest, se condary to the inhibition of mevalonate pathway activities. Mevinolin, a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HM G-CoA) reductase activity, depletes cells of the intermediate products of the pathway that are required for the posttranslational modificati on of proteins, a process giving the proteins lipophilic anchors that bind to membranes. As a consequence, nuclear lamins and ras oncoprotei ns remain in nascent states, and cells' do not proliferate. gamma-Toco trienol, perillyl alcohol, geraniol and d-limonene suppress hepatic HM G-CoA reductase activity, a rate-limiting step in cholesterol synthesi s, and modestly lower serum-cholesterol levels of animals. These isopr enoids also suppress tumor growth. The HMG-CoA reductase of neoplastic tissues differs from that of sterologenic tissues in being markedly r esistant to sterol feedback inhibition. Our review suggests that the m evalonate pathway of tumor tissues is uniquely sensitive to the inhibi tory actions of the dietary isoprenoids.