INTRODUCTION: Mevalonate and derivatives of mevalonate metabolism play important roles in cellular metabolism and may be especially important in rapidly growing cancer cells. A method for delivering mevalonate to extrahepatic tissues, where many tumors of interest in experimental cancer research are found, has not been reported. METHODS: Mice were administered mevalonate subcutaneously via implanted Alzet mini-osmotic pumps. Microsomes isolated from samples of liver, mammary gland, and colon were assayed for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. This enzyme is responsible for endogenous mevalonate synthesis, and its down-regulation is evidence that mevalonate has reached the tissue. Serum cholesterol levels were determined to exclude the possibility that down-regulation of HMG-CoA reductase was caused by an influx of circulating cholesterol. RESULTS: HMG-CoA reductase activity was decreased in livers, mammary glands, and colons of mice given mevalonate via mini-osmotic pumps. Serum cholesterol levels did not rise in these mice, precluding an indirect effect of serum lipoproteins on HMG-CoA reductase regulation. DISCUSSION: Mevalonate can be effectively delivered to cells of the mammary gland and colon of mice via subcutaneously implanted mini-osmotic pumps.
INTRODUCTION:Mevalonate and derivatives of mevalonate metabolism play important roles in cellular metabolism and may be especially important in rapidly growing cancer cells. A method for delivering mevalonate to extrahepatic tissues, where many tumors of interest in experimental cancer research are found, has not been reported. METHODS:Mice were administered mevalonate subcutaneously via implanted Alzet mini-osmotic pumps. Microsomes isolated from samples of liver, mammary gland, and colon were assayed for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. This enzyme is responsible for endogenous mevalonate synthesis, and its down-regulation is evidence that mevalonate has reached the tissue. Serum cholesterol levels were determined to exclude the possibility that down-regulation of HMG-CoA reductase was caused by an influx of circulating cholesterol. RESULTS:HMG-CoA reductase activity was decreased in livers, mammary glands, and colons of mice given mevalonate via mini-osmotic pumps. Serum cholesterol levels did not rise in these mice, precluding an indirect effect of serum lipoproteins on HMG-CoA reductase regulation. DISCUSSION: Mevalonate can be effectively delivered to cells of the mammary gland and colon of mice via subcutaneously implanted mini-osmotic pumps.