Abstract
Activating mutations of Ki‐ras have been detected in most human pancreatic adenocarcinomas. Since Ras protein requires farnesylation to function, we investigated the effects of manumycin, a potent farnesyl:protein transferase inhibitor, on the growth in nude mice of a human pancreatic cancer cell line, MIA PaCa‐2, with a point mutation in the Ki‐ras gene. Tumor‐bearing mice received intraperitoneal injection of 1 or 5 mg/kg manumycin daily for 5 days, or 2 mg/kg manumycin daily for 2 weeks. Growth of inoculated tumors was significantly inhibited by the treatment. The treatment significantly (P<0.05) lowered the numbers of bromodeoxyuridine‐incorporating tumor cells. Manumycin did not have apparent hepatotoxicity in vivo. Farnesyl:protein transferase inhibitors could offer a new approach for cancer chemotherapy.
Keywords: Farnesyl:protein transferase inhibitor, Manumycin, Pancreatic cancer, Nude mouse, Ras
Full Text
The Full Text of this article is available as a PDF (251.2 KB).
REFERENCES
- 1).Barbacid , M.ras genes . Annu. Rev. Biochem. 56 , 779 – 829 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 2).Der , C. J. and Cox , A. D.Isoprenoid modification and plasma membrane association: critical factors for ras oncogenicity . Cancer Cells 3 , 331 – 337 ( 1991. ). [PubMed] [Google Scholar]
- 3).Reiss , Y. , Goldstein , J. L. , Seabra , M. C. , Casey , P. J. and Brown , M. S.Inhibition of purified p21ras farnesyl:protein transferase by Cys‐AAX tetrapeptides . Cell 62 , 81 – 88 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 4).Schaber , M. D. , O'Hara , M. B. , Grarsky , V. M. , Mosser , S. D. , Bergstrom , J. D. , Moores , S. L. , Marshall , M. S. , Friedman , P. A. , Dixon , R. A. F. and Gibbs , J. B.Polyisoprenylation of Ras in vitro by a farnesyl‐protein transferase . J. Biol. Chem. 265 , 14701 – 14704 ( 1990. ). [PubMed] [Google Scholar]
- 5).Gibbs , J. B.Ras C‐terminal processing enzymes—new drug targets ? Cell 65 , 1 – 4 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 6).Kawata , S. , Kakimoto , H. , Ishiguro , H. , Yamasaki , E. , Inui , Y. and Matsuzawa , Y.Effect of pravastatin, a potent 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitor, on survival of AH 130 hepatoma‐bearing rats . Jpn. J. Cancer Res. 83 , 1120 – 1123 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7).Kawata , S. , Nagase , T. , Yamasaki , E. , Ishiguro , H. and Matsuzawa , Y.Modulation of the mevalonate pathway and cell growth by pravastatin and d‐limonene in a human hepatoma cell line (Hep G2) . Br. J. Cancer 69 , 1015 – 1020 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8).Ruch , R. J. and Sigler , K.Growth inhibition of rat liver epithelial tumor cells by monoterpenes does not involve Ras plasma membrane association . Carcinogenesis 15 , 787 – 789 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 9).Kohl , N. E. , Mosser , S. D. , de Solms , S. J. , Giuliani , E. A. , Pompliano , D. L. , Graham , S. L. , Smith , R. L. , Scolnik , E. M. , Oliff , A. and Gibbs , J. B.Selective inhibitors of ras‐dependent transformation by a farnesyl‐transferase inhibitor . Science 260 , 1934 – 1937 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 10).James , G. L. , Goldstein , J. L. , Brown , M. S. , Rawson , T. E. , Somers , T. C. , McDowell , R. S. , Crowley , C. W. , Lucas , B. K. , Levinson , A. D. and Marster , J. C. , Jr.Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells . Science 260 , 1937 – 1942 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 11).Hara , M. , Akasaka , K. , Akinaga , S. , Okabe , M. , Nakano , H. , Gomez , R. , Wood , D. , Uh , M. and Tamanoi , F.Identification of Ras farnesyltransferase inhibitors by microbial screening . Proc. Natl. Acad. Sci. USA 90 , 2281 – 2285 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12).Gibbs , J. B. , Pompliano , D. L. , Mosser , S. D. , Rands , E. , Lingham , R. B. , Singh , S. B. , Scolnick , E. M. , Kohl , N. E. and Oliff , A.Selective inhibitor of farnesyl‐protein transferase blocks ras processing in vivo . J. Biol. Chem. 268 , 7617 – 7620 ( 1993. ). [PubMed] [Google Scholar]
- 13).Omura , S. , van der Pyl , D. , Inokoshi , J. , Takahashi , Y. and Takeshima , H.Pepticinnamins, new farnesyl‐protein transferase inhibitors produced by an actinomycete. I. Producing strain, fermentation, isolation and biological activity . J. Antibiot. 46 , 222 – 228 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 14).Yunis , A. A. , Arimura , G. K. and Russin , D. J.Human pancreatic carcinoma MIA PaCa‐2 in continuous culture: sensitivity to asparaginase . Int. J. Cancer 19 , 128 – 135 ( 1977. ). [DOI] [PubMed] [Google Scholar]
- 15).Quaife , C. J. , Pinkert , C. A. , Ornitz , D. M. , Palmiter , R. D. and Brinster , R. L.Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice . Cell 48 , 1023 – 1034 ( 1987. ). [DOI] [PubMed] [Google Scholar]