Abstract
N‐(N‐(L‐3‐frans‐carboxyoxiran‐2‐carbonyl)‐L‐leucyl)‐agmatine (E‐64), a thiol protease inhibitor, potentiated the cytotoxicity of peplomycin against the Chinese hamster lung (V79) cell. After the treatment of the cells with E‐64 (50 μg/ml) for 12 h, bleomycin hydrolasc activity of the cells was almost completely inhibited. V79 cells treated with [3H]peplomycin for 24 h in the presence of E‐64 (50 μg/ml) accumulated twice as much [3H]peplomycin and five times less [3H]desamidopeplomycin compared with V79 cells treated in the absence of E‐64. These results suggest that E‐64 increases the sensitivity of V79 cells to peplomycin probably by inhibiting the intracellular bleomycin hydrolasc activity.
Keywords: Peplomycin, E‐64, Synergism, Bleomycin hydrolase
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REFERENCES
- 1. ) Umezawa , H. , Takeuchi , T. , Hori , S. , Sawa , T. , Ishizuka , M. , Ichikawa , T. and Komai , T.Studies on the mechanism of antitumor effect of bleomycin on squamous cell carcinoma . J. Antibiot. , 25 , 409 – 420 ( 1972. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Sugiura , Y. , Muraoka , Y. , Fujii , A. , Takita , T. and Umezawa , H.Chemistry of bleomycin. XXIV. Desamido bleomycin from viewpoint of metal coordination and oxygen activation . J. Antibiot. , 32 , 756 – 758 ( 1979. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Nishimura , C. , Tanaka , N. , Suzuki , H. and Tanaka , N.Purification of bleomycin hydrolase with a monoclonal antibody and its characterization . Biochemistry , 26 , 1574 – 1578 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Sebti , S. M. , De Leon , J. C. and Lazo , J. S.Purification, characterization, and amino acid composition of rabbit pulmonary bleomycin hydrolase . Biochemistry , 26 , 4213 – 4219 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Hanada , K. , Tamai , M. , Yamagishi , M. , Ohmura , S. , Sawada , J. and Tanaka , I.Isolation and characterization of E‐64, a new thiol protease inhibitor . Agric. Biol. Chem. , 42 , 523 – 528 ( 1978. ). [Google Scholar]
- 6. ) Tsuruo , T. , Iida , H. , Tsukagoshi , S. and Sakurai , Y.Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil . Cancer Res. , 41 , 1967 – 1972 ( 1981. ). [PubMed] [Google Scholar]
- 7. ) Nakagawa , M. , Yamaguchi , T. , Fukawa , H. , Ogata , J. , Komiyama , S. , Akiyama , S. and Kuwano , M.Potentiation by squalene of the cytotoxicity of anticancer agents against cultured mammalian cells and murine tumor . Jpn. J. Cancer Res. 76 , 315 – 320 ( 1985. ). [PubMed] [Google Scholar]
- 8. ) Akiyama , S. and Kuwano , M.Antitumor effect of a combination of 6‐methylthioinosine and amphotericin B on mouse leukemia L1210 . Cancer Lett. , 9 , 305 – 311 ( 1980. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Takayama , H. , Itoh , M. , Mizuguchi , S. , Abuki , H. , Ishibashi , M. and Miyazaki , H.Absorption, excretion, distribution and metabolism of 3H‐labeled peplomycin sulfate . Jpn. J. Antibiot. , 31 , 895 – 909 ( 1978. ). [PubMed] [Google Scholar]
- 10. ) Akiyama , S. , Ikezaki , K. , Kuramochi , H. , Takahashi , K. and Kuwano , M.Bleomycin‐resistant cells contain increased bleomycin‐hydrolase activities . Biochem. Biophys. Res. Commun. , 101 , 55 – 60 ( 1981. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Lazo , J. S. , Boland , C. J. and Schwartz , P. E.Bleomycin hydrolase activity and cytotoxicity in human tumors . Cancer Res. , 42 , 4026 – 4031 ( 1982. ). [PubMed] [Google Scholar]
- 12. ) Ozawa , S. , Tamura , A. , Suzuki , H. , Nishimura , T. and Tanaka , N.Mechanisms affecting peplomycin sensitivity of Chinese hamster cell lines . J Antibiot. , 38 , 1257 – 1265 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Nishimura , C. , Nishimura , T. , Tanaka , N. and Suzuki , H.Potentiation of the cytotoxicity of peplomycin against Ehrlich ascites carcinoma by bleomycin hydrolase inhibitors . J. Antibiot. , 40 , 1794 – 1795 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 14. ) Wise , R. , Andrews , J. M. and Bedford , K. A.In vitro study of clavulanic acid in combination with penicillin, amoxycillin, and carbenicillin . Antimicrob. Agents Chemother. , 13 , 389 – 393 ( 1978. ). [DOI] [PMC free article] [PubMed] [Google Scholar]