INHIBITION OF LUNG-TUMOR CELL-GROWTH IN-VITRO AND MOUSE LUNG-TUMOR FORMATION BY LOVASTATIN

The HMG-CoA reductase inhibitor, lovastatin (LOV), has been reported t o inhibit Ras farnesylation and the growth of Ras-transformed cells. M ouse lung tumors and human lung adenocarcinomas often have activating mutations in K-ras alleles. In the present study, we determined whethe r LOV inhibited the growth in vitro of mouse (C10, E9, LM1, LM2, and 8 2-132) and human (NCI-H125, H292, H441, H460, and H661) non-transforme d and neoplastically transformed lung epithelial cells and whether gro wth inhibition was related to cell transformation or K-ras activation. LOV inhibited the growth of mouse and human lung cells, but cell sens itivities were unrelated to neoplastic transformation or K-ras mutatio n. In addition, we evaluated whether LOV could inhibit the formation o f lung adenomas induced by the tobacco-specific nitrosamine, -(N-methy l-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mice. LOV was admin istered in the diet at 0, 40, 160, or 400 ppm ad libitum to male strai n A/J mice beginning 1 week after lung tumor induction with NNK (10 mu mol/mouse). Mice were euthanized 6 months later. Enumeration of lung tumors revealed that LOV did not affect tumor incidence or size, but s ignificantly reduced tumor multiplicity in a dose-related manner. Thes e data suggest that LOV can suppress the formation of NNK-induced lung tumors, possibly at an early promotional stage. This suppression does not appear to be related to either the presence of mutated K-ras or t o changes in K-ras expression.