Skip to main content
SpringerLink
Log in

Effects of the new mitotic inhibitor pyrimidinsulfone NY 4137 on human cells in vitro and on colchicine binding to tubulin

  • Preclinical Studies
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Abstract

The effect of 2-(2-thenyl)sulfonyl-5-bromopyrimidine (NY 4137) on cells of the human line NHIK 3025 was investigated. It was shown that NY 4137 induces cell cycle specific inhibition in metaphase. A dose-dependent prolongation of metaphase was found and the fraction of cells able to escape metaphase arrest declined gradually as the concentration of NY 4137 increased. A total block in metaphase was achieved with 0.016 mM and higher concentrations of NY 4137. Interphase was also prolonged in cells treated with 0.016 mM. Inhibition of valine incorporation by NY 4137 was also found to be dose-dependent. Following a 2-h exposure to 0.2 mM NY 4137 valine incorporation was inhibited by 80–85%. Inhibition of colchicine and vincristine binding to purified tubulin was also investigated. Double reciprocal plot and gel filtration chromatography showed that NY 4137 competitively inhibited colchicine binding to DEAE-cellulose purified tubulin. NY 4137 had no effect on vincristine binding to tubulin. The binding of NY 4137 to tubulin at or near the colchicine binding site may be responsible for the metaphase arrest.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Oftebro R, Grimmer Ø, Øyen TB, Laland SG: 5-fluoropyrimidin-2-one, a new metaphase arresting agent. Biochem Pharmacol 21:2451–2456, 1972

    Google Scholar 

  2. Sørensen AC, Østvold AC, Laland SG, Lindmo T, Oftebro R: Escape from metaphase arrest by Ehrlich ascites cells grown in vitro during treatment with 5-chloropyrimidin-2-one. Biochem Pharmacol 28:3680–3682, 1979

    Google Scholar 

  3. Wibe E, Oftebro R, Christensen T, Laland SG, Pettersen EO, Lindmo T: Inhibitory effects of the new mitotic inhibitor 5-chloropyrimidin-2-one and of vincristine on human cells in vitro. Cancer Res 38:560–565, 1978

    Google Scholar 

  4. Gacek M, Undheim K, Oftebro R, Laland SG: Metahalones, a new class of metaphase inhibitors. FEBS Lett 98:355–358, 1979

    Google Scholar 

  5. Wibe E, Oftebro R, Laland SG, Pettersen EO, Lindmo T: Cell-cycle inhibitory effects of the mitotic inhibition NY 3170 on human cells in vitro. Br J Cancer 39:391–397, 1979

    Google Scholar 

  6. Wibe E, Oftebro R: Inactivation by the mitotic inhibitor NY 4137 of human cells in vitro. Br J Cancer 40:222–227, 1979

    Google Scholar 

  7. Dornish JM, Oftebro R: Structure-activity relationship of 1-propargyl-5-halopyrimidin-2-ones. Invest New Drugs 1:203–211, 1983

    Google Scholar 

  8. Dornish JM, Pettersen EO, Oftebro R: Interaction of 1-propargyl-5-cloropyrimidin-2-one (metahalone) with rat brain tubulin. Biochem Biophys Acta 797:156–162, 1984

    Google Scholar 

  9. Pettersen EO, Nome O, Dornish JM, Oftebro R: Mitotic arrest and interphase inhibition induced by the pyrimidine sulfoxide NY 4138. Invest New Drugs 3: 245–253, 1985

    Google Scholar 

  10. Nordbye K, Oftebro R: Establishment of four new cell strains from human uterine cervix. II. Exp Cell Res 58:458, 1969

    Google Scholar 

  11. Oftebro R, Nordbye K: Establishment of four new cell strains from human uterine cervix. II. Exp Cell Res 58:459–460, 1969

    Google Scholar 

  12. Wibe E, Lindmo T, Kaalhus O: Cell kinetic characteristics in different parts of multicellular spheroids of human origin. Cell Tissue Kinet 14:639–651, 1981

    Google Scholar 

  13. Puck TT, Cieciura SJ, Fisher HW: Clonal growth in vitro of human cells with fibroblastic morphology. J Exp Med 106:145–165, 1957

    Google Scholar 

  14. Pettersen EO, Bakke O, Lindmo T, Oftebro R: Cell cycle characteristics of synchronized and asynchronous population of human cells and effect of cooling and selected mitotic cells. Cell Tissue Kinet 10:511–522, 1977

    Google Scholar 

  15. Engelberg J: A method of measuring the degree of synchronization of cell populations. Exp Cell Res 23:218–227, 1961

    Google Scholar 

  16. Bakke O, Pettersen EO: A fast and accurate method for calculating Engelberg's synchronization index. Cell Tissue Kinet 9:389–393, 1976

    Google Scholar 

  17. Lindmo T, Pettersen EO: Delay of cell cycle progression after X-irradiation of synchronized populations of human cells (NHIK 3025) in culture. Cell Tissue Kinet 12:43–57, 1979

    Google Scholar 

  18. Lindmo T, Steen HB: Flowcytometric measurement of the polarization of fluorescence from intracellular fluorescein in mammalian cells. Biophys J 18:173, 1977

    Google Scholar 

  19. Rønning ØW, Lindmo T, Pettersen EO, Seglen PO: Kinetics of entry into S-phase and into the G1-phase of the subsequent cell cycle for synchronized NHIK 3025 cells. In: Lærum OD, Lindmo T, Thorud, E (eds): Flow Cytometry IV. Universitetsforlaget, Oslo, 1980, pp 350–353

    Google Scholar 

  20. Oftebro R, Laland P, Dedichen J, Laland S, Thorsdalen N: The presence in mammalian liver and blood of substances which inhibit the mitotic activity of human cells in vitro. Br J Cancer 17:183–193, 1963

    Google Scholar 

  21. Nærbø-Dahl W, Oftebro R, Pettersen EO, Brustad T: Inhibitory and cytotoxic effects of oncovin (vincristine sulfate) on cells of human line NHIK 3025. Cancer Res 36:3101–3105, 1976

    Google Scholar 

  22. Rønning ØW, Pettersen EO, Seglen PO: Protein synthesis and protein degradation through the cell cycle of human NHIK 3025 cells in vitro. Exp Cell Res 123:63–72, 1979

    Google Scholar 

  23. Eipper BA: Rat brain microtubule protein: purification and determination of covalently bound phosphate and carbohydrate. Proc Natl Acad Sci USA 69:2283–2287, 1972

    Google Scholar 

  24. Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophase T4. Nature (London) 227:680–685, 1970

    Google Scholar 

  25. Lin CM, Hamel E, Wolpert-DeFilippes MK: Binding to maytansine to tubulin: competition with other mitotic inhibitors. Res Commun Chem Pathol Pharmacol 31:443–451, 1981

    Google Scholar 

  26. Borisy GG: A rapid method for quantitative determination of microtubule protein using DEAE-cellulose filters. Anal Biochem 50:373–385, 1972

    Google Scholar 

  27. Benneche T, Gacek MJ, Undheim K: Pyrimidine-2-sulphides and their S-oxides for use in medicine and methods of use therefore, pharmaceutical compositions containing them, processes for their preparation and such compounds when novel per se. Eur Pat Appl 33:195, 1981

    Google Scholar 

  28. Van Putten LM, Keizer HJ, Mulder JH: Perspectives in cancer research. Synchronization in tumor chemotherapy. Eur J Cancer 12:79–85, 1976

    Google Scholar 

  29. Shelanski ML, Taylor EW: Isolation of a protein subunit from microtubules. J Cell Biol 34:549–554, 1976

    Google Scholar 

  30. Weisenberg RC, Borisy GG, Taylor EW: The colchicine-binding protein of mammalian brain and its relation to microtubules. Biochemistry 7:4469–4479, 1968

    Google Scholar 

  31. Wilson L, Bramburg JR, Mizel SB, Grisham LM, Creswell KM: Interaction of drugs with microtubule proteins. Fed Proc 33:158–166, 1974

    Google Scholar 

  32. Bryan J: Definition of three classes of binding sites in isolated microtubule crystals. Biochemistry 11:2611–2616, 1972

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Tissue Culture, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310, 3, Oslo, Norway

    Mina E. Holm Nygaard, John M. Dornish & Reidar Oftebro

  2. Chemical Institute, University of Oslo, Blindern, 0315, 3, Oslo, Norway

    Kjell Undheim

  3. Fellow of the Norwegian Cancer Society (Landsforeningen mot Kreft), Norway

    John M. Dornish

Authors
  1. Mina E. Holm Nygaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John M. Dornish
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reidar Oftebro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kjell Undheim
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nygaard, M.E.H., Dornish, J.M., Oftebro, R. et al. Effects of the new mitotic inhibitor pyrimidinsulfone NY 4137 on human cells in vitro and on colchicine binding to tubulin. Invest New Drugs 4, 221–229 (1986). https://doi.org/10.1007/BF00179587

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00179587

Key words

Search

Navigation