THE EFFECT OF LOVASTATIN ON [H-3] THYMIDINE UPTAKE IN HTC-4 AND LLC-L1 TUMOR-CELLS

Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibito r, has been shown to inhibit the in vitro and in vivo growth of a numb er of different cell lines. However, the mechanism by which lovastatin exerts its effect is not clear. In this experiment, we investigated t he effect of lovastatin on the incorporation of [H-3]thymidine by Hepa toma Tissue Culture4 (HTC-4) and Lewis Lung Carcinoma L-1 (LLC-L1) tum or cells. Tumor cells were grown under standard conditions and treated with four different concentrations of lovastatin. Cell growth was eva luated by daily hemacytometer cell counts. On Day 4, the plates were p ulsed with 10 mu Ci [H-3]thymidine. After 24 hr, the plates were harve sted and [H-3]thymidine incorporation was measured by scintillation co unting. Lovastatin inhibited both HTC-4 and LLC-L1 cell growth in a do se-dependent manner. At the highest lovastatin dose, both LLC-L1 and H TC-4 cell growth was slowed to less than 15% of control. Remarkably, h owever, both cell lines showed a paradoxical, dose related, increase i n [3H]thymidine uptake. Cell cycle analysis using how cytometry was pe rformed on Day 5 in the LLC-L1 cell line. As the lovastatin concentrat ion increased, a lower percentage of cells was found in the G(1) phase of the cell cycle and a higher percentage of cells was found in the S and G(2) phases. These findings suggest that these tumor cells are un dergoing brisk DNA repair or that lovastatin is more effectively block ing cell division than cellular DNA replication. (C) 1996 Academic Pre ss, Inc.