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. 1983 May;47(5):649–657. doi: 10.1038/bjc.1983.103

Synergistic killing of human leukaemic lymphoblasts by glucocorticoids and cytosine arabinoside.

R M Gledhill, A J Edwards, M R Norman
PMCID: PMC2011387  PMID: 6573907

Abstract

Previous work has shown that the lethal effects of glucocorticoids on the human lymphoblastoid cell line, CEM-C7, are antagonized by the simultaneous presence of 1-beta-D-arabinofuranosylcytosine (Ara-C). A possible cell cycle mechanism prompted further studies using flow microfluorimetry. We now report that (1) Ara-C (10-100 nM) blocks cells in S-phase and (2) the block is reversible after the drug is removed. A second treatment protocol, in which glucocorticoid is added to cells recovering from the effects of 24 h exposure to Ara-C, results in a clear synergism between the 2 drugs. This synergism is observed over a range of concentrations (5-100 nM), but is most significant at low doses, where inhibition of cell growth by Ara-C occurs but cell killing is minimal. Prior treatment with Ara-C increases the number of cells killed in the presence of steroid during the period 12-24 h after removal of the S-phase block. Combinations of Ara-C and steroid can thus be either synergistic or antagonistic, depending on the drug scheduling.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bakke O., Eik-Nes K. B. Cell cycle-specific glucocorticoid growth regulation of a human cell line (NHIK 3025). J Cell Physiol. 1981 Dec;109(3):489–496. doi: 10.1002/jcp.1041090315. [DOI] [PubMed] [Google Scholar]
  2. Benedict W. F., Harris N., Karon M. Kinetics of 1-beta-D-arabinofuranosylcytosine-induced chromosome breaks. Cancer Res. 1970 Oct;30(10):2477–2483. [PubMed] [Google Scholar]
  3. Bhuyan B. K., Fraser T. J., Gray L. G., Kuentzel S. L., Neil G. L. Cell-kill kinetics of several S-phase-specific drugs. Cancer Res. 1973 Apr;33(4):888–894. [PubMed] [Google Scholar]
  4. Cozzarelli N. R. The mechanism of action of inhibitors of DNA synthesis. Annu Rev Biochem. 1977;46:641–668. doi: 10.1146/annurev.bi.46.070177.003233. [DOI] [PubMed] [Google Scholar]
  5. Crissman H. A., Tobey R. A. Cell-cycle analysis in 20 minutes. Science. 1974 Jun 21;184(4143):1297–1298. doi: 10.1126/science.184.4143.1297. [DOI] [PubMed] [Google Scholar]
  6. Early A. P., Preisler H. D., Slocum H., Rustum Y. M. A pilot study of high-dose 1-beta-D-arabinofuranosylcytosine for acute leukemia and refractory lymphoma: clinical response and pharmacology. Cancer Res. 1982 Apr;42(4):1587–1594. [PubMed] [Google Scholar]
  7. Ernst P., Killmann S. A. Perturbation of generation cycle of human leukemic blast cells by cytostatic therapy in vivo: effect of corticosteroids. Blood. 1970 Dec;36(6):689–696. [PubMed] [Google Scholar]
  8. FOLEY G. E., LAZARUS H., FARBER S., UZMAN B. G., BOONE B. A., MCCARTHY R. E. CONTINUOUS CULTURE OF HUMAN LYMPHOBLASTS FROM PERIPHERAL BLOOD OF A CHILD WITH ACUTE LEUKEMIA. Cancer. 1965 Apr;18:522–529. doi: 10.1002/1097-0142(196504)18:4<522::aid-cncr2820180418>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  9. Fried J., Perez A. G., Doblin J. M., Clarkson B. D. Cytotoxic and cytokinetic effects of 1-beta-D-arabinofuranosylcytosine, daunorubicin, and 6-thioguanine on HeLa cells in culture. Cancer Res. 1981 Mar;41(3):1127–1132. [PubMed] [Google Scholar]
  10. Galili U., Leizerowitz R., Moreb J., Gamliel H., Gurfel D., Polliack A. Metabolic and ultrastructural aspects of the in vitro lysis of chronic lymphocytic leukemia cells by glucocorticoids. Cancer Res. 1982 Apr;42(4):1433–1440. [PubMed] [Google Scholar]
  11. Gledhill R. M., Norman M. R. Antagonism of drugs used in leukaemia therapy to the killing of human lymphoblastoid cells by steroid. Br J Cancer. 1981 Sep;44(3):467–471. doi: 10.1038/bjc.1981.208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Graham F. L., Whitmore G. F. Studies in mouse L-cells on the incorporation of 1-beta-D-arabinofuranosylcytosine into DNA and on inhibition of DNA polymerase by 1-beta-D-arabinofuranosylcytosine 5'-triphosphate. Cancer Res. 1970 Nov;30(11):2636–2644. [PubMed] [Google Scholar]
  13. Graham F. L., Whitmore G. F. The effect of-beta-D-arabinofuranosylcytosine on growth, viability, and DNA synthesis of mouse L-cells. Cancer Res. 1970 Nov;30(11):2627–2635. [PubMed] [Google Scholar]
  14. Harmon J. M., Norman M. R., Fowlkes B. J., Thompson E. B. Dexamethasone induces irreversible G1 arrest and death of a human lymphoid cell line. J Cell Physiol. 1979 Feb;98(2):267–278. doi: 10.1002/jcp.1040980203. [DOI] [PubMed] [Google Scholar]
  15. Harrap K. R., Riches P. G., Gilby E. D., Sellwood S. M., Wilkinson R., Konyves I. Studies on the toxicity and antitumour activity of prednimustine, a prednisolone ester of chlorambucil. Eur J Cancer. 1977 Aug;13(8):873–881. doi: 10.1016/0014-2964(77)90143-8. [DOI] [PubMed] [Google Scholar]
  16. Jones P. A., Baker M. S., Benedict W. F. The effect of 1-beta-D-arabinofuranosylcytosine on cell viability, DNA synthesis, and chromatid breakage in synchronized hamster fibrosarcoma cells. Cancer Res. 1976 Oct;36(10):3789–3797. [PubMed] [Google Scholar]
  17. Karon M., Benedict W. F., Rucker N. Mechanism of 1- -D-arabinofuranosylcytosine-induced cell lethality. Cancer Res. 1972 Dec;32(12):2612–2615. [PubMed] [Google Scholar]
  18. Keating M. J., Smith T. L., McCredie K. B., Bodey G. P., Hersh E. M., Gutterman J. U., Gehan E., Freireich E. J. A four-year experience with anthracycline, cytosine arabinoside, vincristine and prednisone combination chemotherapy in 325 adults with acute leukemia. Cancer. 1981 Jun 15;47(12):2779–2788. doi: 10.1002/1097-0142(19810615)47:12<2779::aid-cncr2820471204>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  19. Kufe D. W., Major P. P., Egan E. M., Beardsley G. P. Correlation of cytotoxicity with incorporation of ara-C into DNA. J Biol Chem. 1980 Oct 10;255(19):8997–8900. [PubMed] [Google Scholar]
  20. Lampkin B. C., Nagao T., Mauer A. M. Drug effect in acute leukemia. J Clin Invest. 1969 Jun;48(6):1124–1130. doi: 10.1172/JCI106069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Major P. P., Sargent L., Egan E. M., Kufe D. W. Correlation of thymidine-enhanced incorporation of ara-C in deoxyribonucleic acid with increased cell kill. Biochem Pharmacol. 1981 Aug 15;30(16):2221–2224. doi: 10.1016/0006-2952(81)90091-5. [DOI] [PubMed] [Google Scholar]
  22. Meyn R. E., Meistrich M. L., White R. A. Cycle-dependent anticancer drug cytotoxicity in mammalian cells synchronized by centrifugal elutriation. J Natl Cancer Inst. 1980 May;64(5):1215–1219. [PubMed] [Google Scholar]
  23. Momparler R. L. A model for the chemotherapy of acute leukemia with 1-beta-D-arabinofuranosylcytosine. Cancer Res. 1974 Aug;34(8):1775–1787. [PubMed] [Google Scholar]
  24. Momparler R. L. Kinetic and template studies with 1- -D-arabinofuranosylcytosine 5'-triphosphate and mammalian deoxyribonucleic acid polymerase. Mol Pharmacol. 1972 May;8(3):362–370. [PubMed] [Google Scholar]
  25. Moore R. C. Effects of 1-beta-D-arabinofuranosylcytosine on chromosomes, depending upon the cell cycle stage at the time of exposure. Mutat Res. 1981 Oct;83(3):361–374. doi: 10.1016/0027-5107(81)90018-x. [DOI] [PubMed] [Google Scholar]
  26. Munck A., Crabtree G. R., Smith K. A. Glucocorticoid receptors and actions in rat thymocytes and immunologically stimulated human peripheral lymphocytes. Monogr Endocrinol. 1979;12:341–355. doi: 10.1007/978-3-642-81265-1_19. [DOI] [PubMed] [Google Scholar]
  27. Norman M. R., Harmon J. M., Thompson E. B. Use of a human lymphoid cell line to evaluate interactions between prednisolone and other chemotherapeutic agents. Cancer Res. 1978 Nov;38(11 Pt 2):4273–4278. [PubMed] [Google Scholar]
  28. Norman M. R., Thompson E. B. Characterization of a glucocorticoid-sensitive human lymphoid cell line. Cancer Res. 1977 Oct;37(10):3785–3791. [PubMed] [Google Scholar]
  29. Rivera G., Aur R. J., Dahl G. V., Pratt C. B., Wood A., Avery T. L. Combined VM-26 and cytosine arabinoside in treatment of refractory childhood lymphocytic leukemia. Cancer. 1980 Mar 15;45(6):1284–1288. doi: 10.1002/1097-0142(19800315)45:6<1284::aid-cncr2820450604>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  30. Rivera G., Dahl G. V., Bowman W. P., Avery T. L., Wood A., Aur R. J. VM-26 and cytosine arabinoside combination chemotherapy for initial induction failures in childhood lymphocytic leukemia. Cancer. 1980 Oct 15;46(8):1727–1730. doi: 10.1002/1097-0142(19801015)46:8<1727::aid-cncr2820460804>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  31. Shepherd R., Harrap K. R. Modulation of the toxicity and antitumour activity of alkylating drugs by steroids. Br J Cancer. 1982 Mar;45(3):413–420. doi: 10.1038/bjc.1982.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Simone J. V. Childhood leukemia as a model for cancer research: the Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res. 1979 Nov;39(11):4301–4307. [PubMed] [Google Scholar]
  33. Sloman J. C., Bell P. A. Cell cycle-specific effects of glucocorticoids on phytohaemagglutinin-stimulated lymphocytes. Clin Exp Immunol. 1980 Feb;39(2):503–509. [PMC free article] [PubMed] [Google Scholar]
  34. TROWELL O. A. The culture of lymph nodes in synthetic media. Exp Cell Res. 1955 Oct;9(2):258–276. doi: 10.1016/0014-4827(55)90099-9. [DOI] [PubMed] [Google Scholar]
  35. Tew K. D., Wang A. L., Lindner D. J., Schein P. S. Enhancement of nitrosourea cytotoxicity in vitro using hydrocortisone. Biochem Pharmacol. 1982 Mar 15;31(6):1179–1180. doi: 10.1016/0006-2952(82)90365-3. [DOI] [PubMed] [Google Scholar]
  36. Tobey R. A., Crissman H. A. Use of flow microfluorometry in detailed analysis of effects of chemical agents on cell cycle progression. Cancer Res. 1972 Dec;32(12):2726–2732. [PubMed] [Google Scholar]
  37. Woodcock D. M., Cooper I. A. Evidence for double replication of chromosomal DNA segments as a general consequence of DNA replication inhibition. Cancer Res. 1981 Jun;41(6):2483–2490. [PubMed] [Google Scholar]
  38. Woodcock D. M., Fox R. M., Cooper I. A. Evidence for a new mechanism of cytotoxicity of 1-beta-D arabinofuranosylcytosine. Cancer Res. 1979 Apr;39(4):1418–1424. [PubMed] [Google Scholar]
  39. Yataganas X., Strife A., Perez A., Clarkson B. D. Microfluorimetric evaluation of cell kill kinetics with 1-beta-D-arabinofuranosylcytosine. Cancer Res. 1974 Oct;34(10):2795–2806. [PubMed] [Google Scholar]

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