Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Identification of compounds with preferential inhibitory activity against low-Nm23-expressing human breast carcinoma and melanoma cell lines

Nature Medicine volume 3, pages 395–401 (1997)Cite this article

Abstract

We have used the COMPARE computer algorithm and Nm23 expression as a marker of tumor metastatic potential to examine the in vitro antiproliferative activity of chemotherapeutic drugs on human breast carcinoma and melanoma cell lines. None of 171 compounds in clinical use or under development and only 40 of 30,000 repository compounds exhibited preferential growth inhibition of low-Nm23-expressing, metastatically aggressive cell lines with a Pearson correlation coefficient of ≤0.64. Characterization of one compound, NSC 645306, is presented including in vivo activity in a hollow fiber assay. The data demonstrate a novel approach to drug identification for aggressive human tumors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Monks, A. et al. Feasibility of a high flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J.Natl.Cancer Inst. 83, 757–766 (1991).

    Article  CAS  Google Scholar 

  2. Boyd, M. & Paull, K. Some practical considerations and applications of the National Cancer Institute In vitro Anticancer Drug Discovery Screen. Drug Dev. Res. 34, 91–109 (1995).

    Article  CAS  Google Scholar 

  3. Paull, K. et al. Display and anlysis of patterns of differential activity of drugs against human tumor cell lines: Development of mean graph and COMPARE algorithm. J. Natl. Cancer Inst. 81, 1088–1092 (1989).

    Article  CAS  Google Scholar 

  4. Fitzsimmons, S. et al. Reductase enzyme expression across the National Cancer Institute tumor cell line panel: Correlation with sensitivity to Mitomycin C and EO9. J. Natl. Cancer Inst. 88, 259–269 (1996).

    Article  CAS  Google Scholar 

  5. Paull, K., Lin, C., Malspeis, L. & Hamel, E. Identification of novel antimitotic agents acting at the tubulin level by computer-assisted evaluation of differential cytotoxicity data. Cancer Res. 52, 3892–3900 (1992).

    CAS  PubMed  Google Scholar 

  6. Bai, R. et al. Halichondrin B and Homohalichondrin B, marine natural products binding in the vinca domain of tubulin. J. Biol. Chem. 266, 15882–15889 (1991).

    CAS  PubMed  Google Scholar 

  7. Paull, K., Hamel, E. & Malspeis, L. Prediction of biochemical mechanism of action from the in vitro antitumor screen of the National Cancer Institute, in Cancer ChemotherapeuticAgents. (ed. W.O. Foye) 9–45 (ACS, Washington, DC, 1995).

    Google Scholar 

  8. Weinstein, J.N. et al. An information-intensive approach to the molecular pharmacolocy of cancer. Science (in the press).

  9. Alvarez, M. et al. Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. J. Clin. Invest. 95, 2205–2214 (1995).

    Article  CAS  Google Scholar 

  10. Steeg, P.S. et al. Evidence for a novel gene associated with low tumor metastatic potential. J. Natl. Cancer Inst. 80, 200–204 (1988).

    Article  CAS  Google Scholar 

  11. DeLaRosa, A., Williams, R.L. & Steeg, P.S. Nm23/nucleoside diphosphate kinases: Toward a structural and biochemical understanding of its biological functions. Bioessays 17, 53–62 (1995).

    Article  CAS  Google Scholar 

  12. Leone, A. et al. Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell 65, 25–35 (1991).

    Article  CAS  Google Scholar 

  13. Leone, A., Flatow, U., VanHoutte, K. & Steeg, P.S. Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: Effects on tumor metastatic potential, colonization, and enzymatic activity. Oncogene 8, 2325–2333 (1993).

    CAS  PubMed  Google Scholar 

  14. Parhar, R.S. et al. Effects of cytokine mediated modulation of Nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells. Intl. J. Cancer 60, 204–210 (1995).

    Article  CAS  Google Scholar 

  15. Baba, H. et al. Two isotypes of murine nm23/Nudeoside Diphosphate Kinse, nm23-M1 and nm23-M2, are involved in metastatic suppression of a murine melanoma line. Cancer Res. 55, 1977–1981 (1995).

    CAS  PubMed  Google Scholar 

  16. Fukuda, M. et al. Metastatic potential of rat mammary adenocarcinoma cells associated with decreased expression of nucleoside diphosphate kinase/nm23: Reduction by transfection of NDP Kinase a isoform, an nm23-H2 gene homolog. Intl. J. Cancer

  17. Kantor, J.D., McCormick, B., Steeg, P.S. & Zetter, B.R. Inhibition of cell motility after nm23 transfection of human and murine tumor cells. Cancer Res. 53, 1971–1973 (1993).

    CAS  PubMed  Google Scholar 

  18. Howlett, A.R., Petersen, O.W., Steeg, P.S. & Bissell, M.J. A novel function for Nm23: Overexpression in human breast carcinoma cells leads to the formation of basement membrane and growth arrest. J. Natl. Cancer Inst. 86, 1838–1844 (1994).

    Article  CAS  Google Scholar 

  19. Ferguson, A. et al. Increased sensitivity to cisplatin by nm23-transfected tumor cell lines. Cancer Res. 56, 2931–2935 (1996).

    CAS  PubMed  Google Scholar 

  20. Thompson, E. et al. Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J. Cell Physiol. 150, 534–544 (1992).

    Article  CAS  Google Scholar 

  21. Price, J.E., Polyzos, A., Zhang, R.D. & Daniels, L.M. Tumorigenicity and metastasis of human breast carcinoma Cell lines in nude mice. Cancer Res. 50, 717–721 (1990).

    CAS  PubMed  Google Scholar 

  22. Iliopoulos, D. et al. Inhibition of metastases of a human melanoma xenograft by monoclonal antibody to the GD2/GD3 gangliosides. J. Natl. Cancer Inst. 81, 440–444 (1989).

    Article  CAS  Google Scholar 

  23. Herlyn, D. et al. In vitro properties of human melanoma Cells metastatic in nude mice. Cancer Res. 50, 2296–2302 (1990).

    CAS  PubMed  Google Scholar 

  24. Juhasz, I. et al. Growth and invasion of human melanomas in human skin grafted to immunodeficient mice. Am. J. Pathol. 143, 528–537 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hollingshead, M.G. et al. In vivo cultivation of tumor Cells in hollow fibers. Life Sciences 57, 131–141 (1995).

    Article  CAS  Google Scholar 

  26. Stracke, M.L. et al. Insulin-like growth factors stimulate chemotaxis in human melanoma Cells. Biochemical and BiophysicalResearchCommunications 153, 1076–1083 (1988).

    CAS  Google Scholar 

  27. Theodorescu, D., Caltabiano, M., Grieg, R., Rieman, D. and Kerbel, R.S. Reduction of TGF-beta activity abrogates growth promoting tumor Cell-Cell interactions in vivo. J. Cell. Physiol. 148, 380–390 (1991).

    Article  CAS  Google Scholar 

  28. Schwartz, L.C., Gingras, M., Goldberg, G., Greenberg, A.H. & Wright, J.A. Loss of growth factor dependence and conversion for transforming growth factor B1 inhibition to stimulation in metastatic H-ras transformed murine fibroblasts. Cancer Res. 48, 6999–7003 (1988).

    Google Scholar 

  29. Hafez, M., Infante, D., Winawer, S. & Friedman, E. Transforming growth factor β1 acts as an autocrine growth reglulator in colon enterocytic differentiation but not in goblet Cell maturation. Cell Growth Diff. 1, 617–626 (1990).

    CAS  PubMed  Google Scholar 

  30. Sethi, M. Inhibition of reverse transcriptase activity by benzophenanthridine alkaloids. J. Natural Products 42, 187–196 (1979).

    Article  CAS  Google Scholar 

  31. Tan, G., Pezzuto, J. & Kinghorn, A. Evaluation of natural products as inhibitors of human immunodeficiency viruse type I (HIV-1) reverse transcriptase. J.Natural Products 54, 143–154 (1991).

    Article  CAS  Google Scholar 

  32. Lee, J., MacFarlane, J., Zee-Cheng, R. & Cheng, C. Inhibition of catechol O-methyl-transferase and transfer RNA methyltransferase by Coralyne, nitidine and related compounds. J. Pharmaceutical Sciences 66, 986–989 (1977).

    Article  CAS  Google Scholar 

  33. Sethi, V. Inhibition of mammalian and Oncornavirus nucleic acid polymerase activities by Alkoxybenzophenanthridine alkaloids. Cancer Res. 36, 2390–2395 (1976).

    CAS  PubMed  Google Scholar 

  34. Wang, L.-K., Johnson, R. & Hecht, S. Inhibiton of topoisomerase I function by Nitidine and Fagaronine. Chem. Res. Toxicol. 6, 813–818 (1993).

    Article  CAS  Google Scholar 

  35. Kovacic, P. et al. Charge transferoxy radical mechanism ofr anti-cancer agents. Anti-cancer Drug Design 1, 197–214 (1986).

    CAS  PubMed  Google Scholar 

  36. Suffness, M. & Douros, J., Miscellaneous natrual products with antitumor activity. in Anticancer Agents Based on Natural Product Models. 465–487 (Academic Press, New York, 1980).

    Google Scholar 

  37. Rosengard, A.M. et al. Reduced Nm23/Awd protein in tumor metastasis and aberrant Drosophila development, Nature 342, 177–180 (1989).

    Article  CAS  Google Scholar 

  38. Stermitz, F., Gillespie, J., Amoros, L., Romero, R. & Stermitz, T. Synthesis and biological activity of some antitumor benzophenanthridium salts. J. Med. Chem. 18, 708–715 (1975).

    Article  CAS  Google Scholar 

  39. Benedetti-Doctorvich, V. et al. J. Med. Chem. 37, 711–718 (1994).

    Google Scholar 

  40. Stracke, M.L. et al. Identification, purification, and partial sequencing analysis of autotaxin, a novel motility-stimulating protein. J. Biol. Chem. 267, 2524–2529 (1992).

    CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. José M.P. Freije

    Present address: Deparmento de Bioquimica, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain

  2. Abel De La Rosa

    Present address: Digene Corp., 2301-B Broadbirch Drive, Silver Spring, Maryland, 20904

  3. Michael Grever

    Present address: Department of Oncology, the Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland, 21287-8985

Authors and Affiliations

  1. Women's Cancers Section, Laboratory of Pathology, Division of Clinical Sciences, National Cancer Institute, Building 10, Room 2A33, Bethesda, Maryland, 20892

    José M.P. Freije, Julia A. Lawrence, Abel De La Rosa & Patricia S. Steeg

  2. Biological Testing Branch, Developmental Therapeutics Program, National Cancer Institute, FCRDC, 1003 West 7th Street, Suite 205, Frederick, Maryland, 21702

    Melinda G. Hollingshead

  3. Developmental Therapeutics Program, National Cancer Institute, Executive Plaza North, Room 843, Rockville, Maryland, 20852

    Ven Narayanan, Michael Grever, Edward A. Sausville & Kenneth Paull

Authors
  1. José M.P. Freije
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julia A. Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melinda G. Hollingshead
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abel De La Rosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ven Narayanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Grever
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edward A. Sausville
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kenneth Paull
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Patricia S. Steeg
    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

Freije, J., Lawrence, J., Hollingshead, M. et al. Identification of compounds with preferential inhibitory activity against low-Nm23-expressing human breast carcinoma and melanoma cell lines. Nat Med 3, 395–401 (1997). https://doi.org/10.1038/nm0497-395

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0497-395

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing