REDUCTION OF MOUSE MAMMARY-TUMOR FORMATION AND METASTASIS BY LOVASTATIN, AN INHIBITOR OF THE MEVALONATE PATHWAY OF CHOLESTEROL-SYNTHESIS

Lovastatin, a fungal antibiotic used in the treatment of hypercholeste rolemia, is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A redu ctase, the key regulatory enzyme in the mevalonate pathway of choleste rol synthesis. We examined the antitumor properties of lovastatin on t he F3II sarcomatoid mammary carcinoma, a highly invasive and metastati c murine tumor model. Female BALB/c inbred mice were inoculated subcut aneously with F3II tumor cells and injected i.p. daily with 10 mg/kg b ody weight of lovastatin or administered p.o. at a level corresponding to the human dosage of 1-2 mg/kg/day. Treatment significantly prolong ed tumor latency and reduced tumor formation and metastatic disseminat ion to the lungs from established mammary tumors. In vitro, antitumor properties of lovastatin were strongly associated with inhibition of t umor cell attachment and migration. These actions were prevented by ad dition of mevalonate but not by equivalent concentrations of farnesyl pyrophosphate. In accordance, Western blot assays showed that lovastat in effects did not appear to be related to modifications in Ras oncopr oteins in our model. The present data indicate that lovastatin could b e an antitumor agent with potentially useful clinical applications in breast cancer.