Abstract
The mode of antiproliferative action of deoxyspergualin (NKT‐01) was examined. The growth‐inhibitory effect on a murine leukemia cell line L1210 following treatment with NKT‐01 was time‐dependent, and there was little or no effect on the syntheses of DNA and RNA. Thus, the inhibitory activity of NKT‐01 was not attributable to the inhibition of DNA and RNA syntheses. The influence of NKT‐01 on cell cycle progression was studied by flow cytometric analysis. Bromodeoxyuridine/DNA distribution patterns in cells that were treated for 72 h, showed that the growth inhibition is due to the delay of cell cycle progression but not to cytotoxicity. This finding was also supported by evidence that the treated cells were re‐proliferative in fresh medium. In addition, a majority of drug‐treated cells was prevented from traversing from the G0/G1 phase to the S phase by 144 h or longer exposure to NKT‐01. The results suggest that NKT‐01 is cytostatic, preventing G0/G1‐S progression.
Keywords: Deoxyspergualin, Leukemia, G1 arrest
Full Text
The Full Text of this article is available as a PDF (206.1 KB).
REFERENCES
- 1. ) Umeda , Y. , Moriguchi , M. , Kuroda , H. , Nakamura , T. , Linuma , H. , Takeuchi , T. and Umezawa , H.Synthesis and antitumor activity of spergualin analogues. I. Chemical modification of 7‐guanidino‐3‐hydroxyacyl moiety J. Antibiot. , 38 , 886 – 898 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Plowman , J. , Harrison , S. D. , Jr. , Trader , M. W. , Griswold , D. P. , Jr. , Chadwick , M. , McComish , M. F. , Silveira , D. M. and Zaharko , D.Preclinical antitumor activity and pharmacological properties of deoxysper‐gualin . Cancer Res. , 47 , 685 – 689 ( 1987. ). [PubMed] [Google Scholar]
- 3. ) Kuramochi , H. , Hiratsuka , M. , Nagamine , S. , Takahashi , K. , Nakamura , T. , Takeuchi , T. and Umezawa , H.The antiproliferative action of deoxyspergualin is different from that induced by amine oxidase . J. Antibiot. , 41 , 234 – 238 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Nemoto , K. , Hayashi , M. , Sugawara , Y. , Abe , F. , Takita , T. and Takeuchi , T.Effects of deoxyspergualin on hematopoiesis: studies of murine hematopoietic progenitor cell and peripheral blood cell levels . J. Antibiot. , 42 , 312 – 316 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Jiang , H. , Takahara , S. , Takano , Y. , Machida , M. , Iwasaki , A. , Kokado , Y. , Kameoka , H. , Moutabarrik , A. , Ishibashi , M. and Sonoda , T.In vitro immunosuppressive effect of deoxyspergualin . Transplant. Proc. , 22 , 1633 – 1637 ( 1990. ). [PubMed] [Google Scholar]
- 6. ) Nishimura , K. and Tokunaga , TEffects of 15‐deoxy‐spergualin on the induction of cytotoxic T lymphocytes and bone marrow suppression . Transplant. Proceed. , 21 , 1104 – 1107 ( 1989. ). [PubMed] [Google Scholar]
- 7. ) Nishimura , K. and Tokunaga , T.Mechanism of action of 15‐deoxyspergualin I. Suppressive effect on the induction of alloreactive secondary cytotoxic T lymphocytes in vivo and in vitro . Immunology , 68 , 66 – 71 ( 1989. ). [PMC free article] [PubMed] [Google Scholar]
- 8. ) Fujii , H. , Takada , T. , Nemoto , K. , Abe , F. , Fujii , A. and Takeuchi , T.In vitro immunosuppressive properties of spergualins to murine T cell response . J. Antibiot. , 42 , 788 – 794 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Makino , M. , Fujiwara , M. , Watanabe , H. , Aoyagi , T. and Umezawa , H.Immunosuppressive activities of deoxyspergualin. II. The effect on the antibody responses . Immunopharmacology , 14 , 115 – 122 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 10. ) Fujii , H. , Takada , T. , Nemoto , K. , Yamashita , T. , Abe , F. , Fujii , A. and Takeuchi , T.Deoxyspergualin directly suppresses antibody formation in vivo and in vitro . J. Antibiot. , 43 , 213 – 219 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Einat , M. , Resnitzky , D. and Kimchi , A.Close link between reduction of c‐myc expression by interferon and G0/G1 arrest . Nature , 313 , 597 – 600 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Ishioka , C. , Kanamaru , R. , Sato , T. , Dei , T. , Konishi , Y. , Asamura , M. and Wakui , A.Inhibitory effects of pros‐taglandin A2 on c‐myc expression and cell cycle progression in human leukemia cell line HL‐60 . Cancer Res. , 48 , 2813 – 2818 ( 1988. ). [PubMed] [Google Scholar]
- 13. ) Lomo , J. , Holte , H. , Davies , C. L. , Ruud , E. , Laukas , M. , Smeland , E. B. , Godal , T. and Blomhoff , H. K.Down‐regulation of c‐myc RNA is not a prerequisite for reduced cell proliferation, but is associated with G1, arrest in B‐lymphoid cell lines . Exp. Cell Res. , 172 , 84 – 91 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 14. ) Ohsawa , T. and Senshu , T.Exogenous GM1 ganglioside caused G1arrest of human diploid fibroblasts. Flow cytometric studies . Exp. Celt Res. , 173 , 49 – 55 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Dolbeare , F. , Gratzner , H. G. , Pallanicini , M. G. and Gray , J. W.Flow cytometric measurement of total DNA content and incorporated bromodeoxyuridine . Proc. Natl. Acad. Sci. USA , 80 , 5573 – 5575 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. ) Krishan , A , Rapid flow cytometric analysis of mammalian cell cycle by propidium iodide staining . J. Cell Biol , 66 , 188 – 193 ( 1975. ). [DOI] [PMC free article] [PubMed] [Google Scholar]