Abstract
3‐Hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor is known to have an inhibitory effect on cell growth in addition to a cholesterol‐lowering effect. This study examined the effect of pravastatin, a potent inhibitor of HMG‐CoA reductase, on the survival of AH130 hepatoma‐bearing rats. Pravastatin (1, 2, or 8 mg/kg body weight) was intraperitoneally injected once a day into tumor‐bearing rats. The difference in the survival curves was significant between the controls and the rats treated with S mg/kg of pravastatin (P < 0.019 by logrank test) but not between the controls and the rats treated with 1 or 2 mg/kg of the inhibitor. The tumor volume was significantly decreased in the rats treated with 8 mg/kg of pravastatin (P < 0.05). These observations showed that intraperitoneal injection of pravastatin could improve the survival of AH130 hepatoma‐bearing rats and had an inhibitory effect on the growth of the ascites form tumor.
Keywords: Hepatocellular carcinoma, AH 130 hepatoma, Cholesterol biosynthesis, HMG‐CoA reductase
Full Text
The Full Text of this article is available as a PDF (205.5 KB).
REFERENCES
- 1. ) Chen , H. W.The activity of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase and the rate of sterol synthesis diminish in cultures with high cell density. J . Cell Physiol. , 108 , 91 – 97 ( 1981. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Kandutsh , A. A. and Chen , H. W.Consequences of blocked sterol synthesis in cultured cells, DNA synthesis and membrane composition . J. Biol. Chem. , 252 , 409 – 415 ( 1977. ). [PubMed] [Google Scholar]
- 3. ) Siperstein , M. D. and Fagan , V. M.Deletion of the cholesterol‐negative feedback system in liver tumor . Cancer Res. , 24 , 1108 – 1115 ( 1964. ). [PubMed] [Google Scholar]
- 4. ) Kawata , S. , Takaishi , K. , Nagase , T. , Ito , N. , Matsuda , Y. , Tamura , S. , Matsuzawa , Y. and Tarui , S.Increase in the active form of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase in human hepatocellular carcinoma: possible mechanism for alteration of cholesterol biosynthesis . Cancer Res. , 50 , 3270 – 3273 ( 1990. ). [PubMed] [Google Scholar]
- 5. ) Quesney‐Huneeus , V. , Wiley , M. H. and Siperstein , M. D.Essential role for mevalonate synthesis in DNA replication . Proc. Natl. Acad. Sci. USA , 76 , 5056 – 5060 ( 1979. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. ) Goldstein , J. L. and Brown , M. S.Regulation of the mevalonate pathway . Nature , 343 , 425 – 430 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Hancock , J. F. , Magee , A. I. , Childs , J. E. and Marshall , C. J.All ras proteins are polyisoprenylated but only some are palmitoylated . Cell , 57 , 1167 – 1177 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Wolda , S. L. and Glomset , J. A.Evidence for modification of lamin B by a product of mevalonic acid . J. Biol. Chem. , 263 , 5997 – 6000 ( 1988. ). [PubMed] [Google Scholar]
- 9. ) Goldstein , J. L. , Helgeson , J. A. S. and Brown , M. S.Inhibition of cholesterol synthesis with compactin renders growth of cultured cells dependent on the low density lipoprotein receptors . J. Biol Chem. , 254 , 5403 – 5409 ( 1979. ). [PubMed] [Google Scholar]
- 10. ) Habenicht , A. J. R. , Glomset , J. A. and Ross , R.Relation of cholesterol and mevalonic acid to the cell cycle in smooth muscle and Swiss 3T3 cells stimulated to divide by platelet‐derived growth factor . J. Biol. Chem. , 255 , 5134 – 5140 ( 1980. ). [PubMed] [Google Scholar]
- 11. ) Maltese , W. A. , Defendini , R. , Green , R. A. , Sheridan , K. M. and Donley , D.K.Suppression of murine neuroblastoma cells by mevinolin, a competitive inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase . J. Clin. Invest. , 16 , 1748 – 1754 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. ) Kaplan , E. L. and Meier , P.Nonparametric estimation from incomplete observations . J. Am. Stat. Assoc. , 53 , 457 – 481 ( 1958. ). [Google Scholar]
- 13. ) Peto , R. , Pike , M. C. , Armitage , P. , Breslow , N. E. , Cox , D. R. , Howard , S. V. , Mantel , N. , McPherson , K. , Peto , J. and Smith , P. G.Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples . Br. J. Cancer , 35 , 1 – 39 ( 1977. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. ) Folch , J. , Lees , M. and Sloane‐Stanley , G. H.A simple method for the isolation and purification of total lipids from animal tissues . J. Biol Chem. , 226 , 497 – 503 ( 1957. ). [PubMed] [Google Scholar]
- 15. ) Bligh , E. G. and Dyer , W. J.A rapid method of total lipid extraction and purification . Can. J. Biochem. Physiol. , 37 , 911 – 917 ( 1959. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Kawata , S. , Chitranukroh , A. , Owen , J. S. and McIntyre , N.Membrane lipid changes in erythrocytes, liver and kidney in acute and chronic experimental liver disease in rats . Biochim. Biophys. Acta , 896 , 26 – 34 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Siegel , S.The Mann‐Whitney U test . In “ Nonparametric Statistics for the Behavioral Sciences ,” pp. 267 – 294 ( 1956. ). McGraw‐Hill Inc. , New York . [Google Scholar]
- 18. ) Tsujita , Y. , Kuroda , M. , Shimada , Y. , Tanzawa , K. , Arai , M. , Kaneko , I. , Tanaka , M. , Masuda , H. , Tarui , C. , Watanabe , Y. and Fujii , S.Biochim. Biophys. Acta , 877 , 50 – 60 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 19. ) Shinensky , M. , Beck , L. A. , Leonard , S. and Evans , R.Differential inhibitory effects of lovastatin on protein isoprenylation and sterol synthesis . J. Biol. Chem. , 265 , 19937 – 19941 ( 1990. ). [PubMed] [Google Scholar]
- 20. ) DeClue , J. E. , Vass , W. C. , Papageorge , A. G. , Lowry , D. R. and Willumsen , B. M.Inhibition of cell growth by lovastatin is independent of ras function . Cancer Res. , 51 , 712 – 717 ( 1991. ). [PubMed] [Google Scholar]