Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1995 Nov;72(5):1067–1073. doi: 10.1038/bjc.1995.466

Cell cycle-dependent cytotoxicity and induction of apoptosis by liposomal N4-hexadecyl-1-beta-D-arabinofuranosylcytosine.

D H Horber 1, P von Ballmoos 1, H Schott 1, R A Schwendener 1
PMCID: PMC2033964  PMID: 7577448

Abstract

The clonogenic growth inhibition, the cell cycle dependence of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC) cytotoxicity and the capability to induce apoptosis in ara-C-sensitive and -resistant HL-60 cells were investigated and compared with arabinofuranosylcytosine (ara-C). In the clonogenic assay with sensitive HL-60 cells, ara-C was slightly more effective than a liposomal preparation of NHAC, whereas in the resistant cells, NHAC revealed its potency to overcome ara-C resistance, resulting in a 23-fold lower 50% inhibitory concentration compared with ara-C. Cell cycle dependent cytotoxicity and induction of apoptosis were studied by flow cytometry, using the bromodeoxyuridine-propidium iodide and terminal transferase method respectively. In contrast to ara-C, NHAC exerted no phase-specific toxicity at low concentrations (< 40 microM). At higher concentrations the S-phase-specific toxicity increased, probably resulting from ara-C formed from NHAC. NHAC induced apoptosis at higher drug concentrations than ara-C, however apoptosis appeared not to be limited to the S-phase cells. Apoptosis occurred in both cell lines within 2-4 h after drug exposure. These results give further evidence that NHAC exerts its cytotoxicity by different mechanisms of action than ara-C and might therefore be active in ara-C-resistant tumours.

Full text

PDF
1067

Images in this article

1072Figure 4
on p.1072

Selected References

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

  1. Arends M. J., Morris R. G., Wyllie A. H. Apoptosis. The role of the endonuclease. Am J Pathol. 1990 Mar;136(3):593–608. [PMC free article] [PubMed] [Google Scholar]
  2. Berggren M. I., Gallegos A., Dressler L. A., Modest E. J., Powis G. Inhibition of the signalling enzyme phosphatidylinositol-3-kinase by antitumor ether lipid analogues. Cancer Res. 1993 Sep 15;53(18):4297–4302. [PubMed] [Google Scholar]
  3. Bertrand R., Sarang M., Jenkin J., Kerrigan D., Pommier Y. Differential induction of secondary DNA fragmentation by topoisomerase II inhibitors in human tumor cell lines with amplified c-myc expression. Cancer Res. 1991 Dec 1;51(23 Pt 1):6280–6285. [PubMed] [Google Scholar]
  4. Bhalla K., Nayak R., Grant S. Isolation and characterization of a deoxycytidine kinase-deficient human promyelocytic leukemic cell line highly resistant to 1-beta-D- arabinofuranosylcytosine. Cancer Res. 1984 Nov;44(11):5029–5037. [PubMed] [Google Scholar]
  5. Cavazzana M., Calvo F., Facchin P., Barreau P., Geny B., Dal Cortivo L., Dresch C. Use of liquid culture and cell cycle analysis to compare drug damage following in vitro treatment of normal human bone marrow cells with adriamycin, arabinosyl-cytosine, and etoposide. Exp Hematol. 1988 Nov;16(10):876–883. [PubMed] [Google Scholar]
  6. Cohen G. M., Sun X. M., Snowden R. T., Dinsdale D., Skilleter D. N. Key morphological features of apoptosis may occur in the absence of internucleosomal DNA fragmentation. Biochem J. 1992 Sep 1;286(Pt 2):331–334. doi: 10.1042/bj2860331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fietkau R., Friede H., Maurer-Schultze B. Cell kinetic studies of the cytostatic and cytocidal effect of 1-beta-D-arabinofuranosylcytosine on the L1210 ascites tumor. Cancer Res. 1984 Mar;44(3):1105–1113. [PubMed] [Google Scholar]
  8. Frei E., 3rd, Bickers J. N., Hewlett J. S., Lane M., Leary W. V., Talley R. W. Dose schedule and antitumor studies of arabinosyl cytosine (NSC 63878). Cancer Res. 1969 Jul;29(7):1325–1332. [PubMed] [Google Scholar]
  9. Gorczyca W., Bigman K., Mittelman A., Ahmed T., Gong J., Melamed M. R., Darzynkiewicz Z. Induction of DNA strand breaks associated with apoptosis during treatment of leukemias. Leukemia. 1993 May;7(5):659–670. [PubMed] [Google Scholar]
  10. Gorczyca W., Gong J., Ardelt B., Traganos F., Darzynkiewicz Z. The cell cycle related differences in susceptibility of HL-60 cells to apoptosis induced by various antitumor agents. Cancer Res. 1993 Jul 1;53(13):3186–3192. [PubMed] [Google Scholar]
  11. Horber D. H., Ottiger C., Schott H., Schwendener R. A. Pharmacokinetic properties and interactions with blood components of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC) incorporated into liposomes. J Pharm Pharmacol. 1995 Apr;47(4):282–288. doi: 10.1111/j.2042-7158.1995.tb05796.x. [DOI] [PubMed] [Google Scholar]
  12. Horber D. H., Schott H., Schwendener R. A. Cellular pharmacology of a liposomal preparation of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine, a lipophilic derivative of 1-beta-D-arabinofuranosylcytosine. Br J Cancer. 1995 May;71(5):957–962. doi: 10.1038/bjc.1995.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hotz M. A., Gong J., Traganos F., Darzynkiewicz Z. Flow cytometric detection of apoptosis: comparison of the assays of in situ DNA degradation and chromatin changes. Cytometry. 1994 Mar 1;15(3):237–244. doi: 10.1002/cyto.990150309. [DOI] [PubMed] [Google Scholar]
  14. Karon M., Shirakawa S. The locus of action of 1-beta-d-arabinofuranosylcytosine in the cell cycle. Cancer Res. 1969 Mar;29(3):687–696. [PubMed] [Google Scholar]
  15. Kaufmann S. H. Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res. 1989 Nov 1;49(21):5870–5878. [PubMed] [Google Scholar]
  16. Kolla S. S., Studzinski G. P. Constitutive DNA binding of the low mobility forms of the AP-1 and SP-1 transcription factors in HL60 cells resistant to 1-beta-D-arabinofuranosylcytosine. Cancer Res. 1994 Mar 15;54(6):1418–1421. [PubMed] [Google Scholar]
  17. Lacombe F., Belloc F., Bernard P., Boisseau M. R. Evaluation of four methods of DNA distribution data analysis based on bromodeoxyuridine/DNA bivariate data. Cytometry. 1988 May;9(3):245–253. doi: 10.1002/cyto.990090310. [DOI] [PubMed] [Google Scholar]
  18. Lohmeyer M., Workman P. The role of intracellular free calcium mobilization in the mechanism of action of antitumour ether lipids SRI 62-834 and ET18-OMe. Biochem Pharmacol. 1993 Jan 7;45(1):77–86. doi: 10.1016/0006-2952(93)90379-b. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Preisler H. D., Gopal V., Banavali S. D., Finke D., Bokari S. A. Multiparameter assessment of the cell cycle effects of bioactive and cytotoxic agents. Cancer Res. 1992 Aug 1;52(15):4090–4095. [PubMed] [Google Scholar]
  21. Schwendener R. A., Schott H. Treatment of L1210 murine leukemia with liposome-incorporated N4-hexadecyl-1-beta-D-arabinofuranosyl cytosine. Int J Cancer. 1992 May 28;51(3):466–469. doi: 10.1002/ijc.2910510321. [DOI] [PubMed] [Google Scholar]
  22. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  23. Yoshida A., Ueda T., Wano Y., Nakamura T. DNA damage and cell killing by camptothecin and its derivative in human leukemia HL-60 cells. Jpn J Cancer Res. 1993 May;84(5):566–573. doi: 10.1111/j.1349-7006.1993.tb00177.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES