Skip to main content
SpringerLink
Log in

Cell cycle specificity of apoptosis during treatment of leukaemias

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

This review summarizes our observations on the mechanism of induction of apoptosis in vitro in leukaemic cell lines and in vivo in patients with leukaemia undergoing chemotherapy, in relation to the cell cycle. Multiparameter flow cytometric methods allowed us to identify apoptotic cells and position them with respect to their cell cycle phase. Several antitumor agents of different classes have been characterized in terms of the cell cycle phase specificity of induction of apoptosis. Three types of apoptosis could be distinguished in relation to the initial damage to the cell vis-a-vis cell cycle position: (1) homo-phase apoptosis where the cells underwent apoptosis during the same phase in which they were initially affected; (2) homo-cycle apoptosis, where the cells underwent apoptosis during the same cell cycle in which they were initially affected, i.e., prior to or during the first mitosis, and (3) post-mitotic apoptosis, where cells underwent apoptosis during the cell cycle(s) subsequent to that in which the cell was initially affected, most likely at the G1 or G2 checkpoints of these cycle(s). Four ranges of drug concentration can be distinguished in vitro for most drugs, where either: (1) no immediate effects; (2) cytostasis or post-mitotic apoptosis; (3) homo-cycle or homo-phase apoptosis; or (4) necrosis are observed. Analysis of cell death of blast cells from peripheral blood or bone marrow of over 250 leukaemia patients (AML, ALL, CML in blast crisis) treated with various drugs during routine chemotherapy reveals that in the case of DNA topoisomerase inhibitors (e.g., mitoxantrone, VP-16) apoptosis is often rapid (peaks at 1-2 days after drug administration) and has features of homo-phase apoptosis. In contrast, cell death observed after administration of paclitaxel (taxol) or cytarabine (cytosine arabinoside) occurs later and has features of post-mitotic apoptosis: the cells divide but die in G1 of the subsequent cycle(s).

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. Arends MJ, Morris RG, Wyllie AH. Apoptosis: The role of endonuclease. Am J Pathol 1990; 136: 593-608.

    Google Scholar 

  2. Wyllie AH. Apoptosis and the regulation of cell numbers in normal and neoplastic tissues: An overview. Cancer Metast Rev 1992; 11: 95-103.

    Google Scholar 

  3. Wyllie AH, Arends MJ, Morris RG, Walker SW, Evan G. The apoptosis endonuclease and its regulation. Seminars Immunol 1992; 4: 389-398.

    Google Scholar 

  4. Kerr JFR, Winterford CM, Harmon V. Apoptosis. Its significance in cancer and cancer therapy. Cancer 1994; 73: 2013-2026.

    Google Scholar 

  5. Kohn KW, Jackman J, O'Connor PM. Cell cycle control and cancer chemotherapy. J Cell Biochem 1994; 54: 440-452.

    Google Scholar 

  6. Hockenberry DM. bcl-2 in cancer, development and apoptosis. J Cell Sci 1995, 18: 51-55.

    Google Scholar 

  7. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 1995; 146: 3-16.

    Google Scholar 

  8. Darzynkiewicz Z. Apoptosis in antitumor strategies: Modulation of cell cycle and differentiation. J Cell Biochem 1995; 58: 151-159.

    Google Scholar 

  9. Darzynkiewicz Z, Juan G, Li X, Gorczyca W, Murakami T, Traganos F. Cytometry in cell necrobiology: Analysis of apoptosis and accidental cell death (necrosis). Cytometry 1997; 27: 1-20.

    Google Scholar 

  10. Gorczyca W, Bruno S, Darzynkiewicz RJ, Gong J, Darzynkiewicz Z. DNA strand breaks occuring during apoptosis: Their early in situ detection by the terminal deoxynucleotidyl transferase and nick translation assays and prevention by serine protease inhibitors. Int J Oncol 1992; 1: 639-448.

    Google Scholar 

  11. Gorczyca W, Bigman K, Mittelman A, et al. Induction of DNA strand breaks associated with apoptosis during treatment of leukemias. Leukemia 1993; 7: 659-670.

    Google Scholar 

  12. Li X, Gong J, Feldman E, Seiter K, Traganos F, Darzynkiewicz Z. Apoptotic cell death during treatment of leukemias. Leukemia Lymphoma 1994; 13(Suppl): 65-70.

    Google Scholar 

  13. Seiter K, Feldman EJ, Traganos F et al. Evaluation of in vivo induction of apoptosis in patients with acute leukemia treated on a phase I study with Paclitaxel. Leukemia 1995; 9: 1961-1966.

    Google Scholar 

  14. Bhalla K, Ibrado AM, Bradt JE et al. pIXY321 protects against Ara-C or taxol-induced apoptosis and loss of clonogenic survival of normal human bone marrow progenitor cells. Leukemia 1995; 9: 1851-1856.

    Google Scholar 

  15. Raza A, Mundle S, Shetty V et al. Novel insights into biology of myelodysplastic syndromes: excessive apoptosis and role of cytokines. Int J Hematol 1966; 63: 265-276.

    Google Scholar 

  16. Seiter K, Feldman EJ, Halicka HD et al. Phase I clinical and laboratory evaluation of topotecan and cytoarabine in patients with acute leukemia. J Clin Oncol 1966 (in press)

  17. Fisher DE. Apoptosis in cancer therapy: crossing the threshold. Cell 1994; 78: 539-542.

    Google Scholar 

  18. Dive C, Hickmann JA. Drug-target interactions: Only the first step in the commitment to a programmed cell death? Br J Cancer 1991; 64: 192-196.

    Google Scholar 

  19. Oltvai ZN, Korsmeyer SJ. Checkpoints of dueling dimers foil death wishes. Cell 1994; 79: 189-192.

    Google Scholar 

  20. Galaktionov K, Chen X, Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 1996; 382: 511-517.

    Google Scholar 

  21. Evan G, Wyllie AH, Gilbert CS, et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992; 69: 119-128.

    Google Scholar 

  22. Arends MJ, McGregor AH, Toft NJ, et al. Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability. Br J Cancer 1993; 68: 1127-1133.

    Google Scholar 

  23. Harris CC. Structure and function of the p53 tumor suppressor gene: Clues for rational cancer therapeutic strategies. JNCI 1996; 88: 1442-1455.

    Google Scholar 

  24. Bhuyan BK, Groppi VE. Cell cycle specific inhibitors. Pharmac Therap 1989; 42: 307-348.

    Google Scholar 

  25. Gong J, Traganos F, Darzynkiewicz Z. Growth imbalance and altered expression of cyclins B1, A, E and D3 in MOLT-4 cells synchronized in the cell cycle by inhibitors of DNA replication. Cell Growth Diff 1995; 6: 1485-1493.

    Google Scholar 

  26. Gorczyca W, Gong J, Darzynkiewicz Z. Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays. Cancer Res 1993; 52: 1945-1951.

    Google Scholar 

  27. Gold R, Schmied M, Giegerich G, et al. Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques. Lab Invest 1994; 71: 219-225.

    Google Scholar 

  28. Li X, Darzynkiewicz Z. Labelling DNA strand breaks with BdrUTP. Detection of apoptosis and cell proliferation. Cell Prolif 1995; 28: 571-579.

    Google Scholar 

  29. Li X, Melamed MR, Darzynkiewicz Z. Detection of apoptosis and DNA replication by differential labeling of DNA strand breaks with fluorochromes of different color. Exp Cell Res 1996; 222: 28-37.

    Google Scholar 

  30. Darzynkiewicz Z, Li X. Measurements of cell death by flow cytometry. In: Cotter TG, Martin SJ, eds. Techniques in Apoptosis: A User's Guide. London, UK: Portland Press, 1996: 71-106.

    Google Scholar 

  31. 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; 53: 3186-3192.

    Google Scholar 

  32. Bruno S, Lassota P, Giaretti W, Darzynkiewicz Z. Apoptosis of rat thymocytes induced by prednisolone, camptothecin or teniposide is selective to G0 cells and is prevented by inhibitors of proteases. Oncology Res 1992; 4: 29-35.

    Google Scholar 

  33. Kerr JFR, Wyllie AH, Curie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-257.

    Google Scholar 

  34. Gong J, Traganos F, Darzynkiewicz Z. A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal Biochem 1994; 218: 314-319.

    Google Scholar 

  35. D'Arpa P, Beardmore C, Liu LF. Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res 1990; 50: 6919-6924.

    Google Scholar 

  36. Murakami T, Li, X, Gong J, Bhatia U, Traganos F, Darzynkiewicz Z. Induction of apoptosis by 5-azacytidine: Drug concentration-dependent differences in cell cycle specificity. Cancer Res 1995; 55: 3093-3098.

    Google Scholar 

  37. Darzynkiewicz Z, Bruno S, Del Bino G, Traganos F. The cell cycle effects of camptothecin. Ann NY Acad Sci 1996; (in press)

  38. Halicka HD, Ardelt B, Li X, Melamed MR, Darzynkiewicz Z. 2-deoxy-D-glucose enhances sensitivity of human histiocytic lymphoma U937 cells to apoptosis induced by tumor necrosis factor. Cancer Res 1995; 55: 444-449

    Google Scholar 

  39. Darzynkiewicz Z, Williamson B, Carswell EA, Old LJ. Cell cycle specific effects of tumor necrosis factor. Cancer Res 1984; 44: 83-90.

    Google Scholar 

  40. Hotz MA, Traganos F, Darzynkiewicz Z. Changes in nuclear chromatin related to apoptosis or necrosis induced by the DNA topoisomerase II inhibitor fostriecin in MOLT-4 and HL-60 cells are revealed by altered DNA sensitivity to denaturation. Exp Cell Res 1992; 201: 184-191.

    Google Scholar 

  41. Darzynkiewicz Z, Sharpless T, Staiano-Coico L, Melamed MR. Subcompartments of the G1 phase of cell cycle detected by flow cytometry. Proc Natl Acad Sci USA 1980; 77: 6696-6699.

    Google Scholar 

  42. Gong J, Li X, Darzynkiewicz Z. Different patterns of apoptosis of HL-60 cells induced by cycloheximide and camptothecin. J Cell Physiol 1993; 157: 263-270.

    Google Scholar 

  43. Del Bino G, Skierski J, Darzynkiewicz Z. Diverse effects of camptothecin, an inhibitor of topoisomerase I, on the cell cycle of lymphocytic (L1210, MOLT-4) and myelogenous (HL-60, KG1) leukemic cells. Cancer Res 1990; 50: 5746-5750.

    Google Scholar 

  44. Akagi Y, Ito K, Sawada S. Radiation-induced apoptosis and necrosis in Molt-4 cells: a study of dose—effect relationships and their modification. Int J Radiat Biol 1993; 64: 47-56.

    Google Scholar 

  45. Matsubara K, Kubota M, Kuwakado K, et al. Variable susceptibility to apoptosis by calcium ionophore in hybridomas between HL-60 promyelocytic and CEM T-lymphocytic leukemia cell lines: Relationship to constitutive Mg2+-dependent endonuclease. Exp Cell Res 1994; 213: 412-417.

    Google Scholar 

  46. Aller P, Rius C, Mata F, Zorilla A, Cabanas C, Bellon T, Barnabeu C. Camptothecin induces differentiation and stimulates the expression of differentiation-related genes in U-937 promonocytic leukemia cells. Cancer Res 1992; 52: 1245-1251.

    Google Scholar 

  47. Del Bino G, Skierski JS, Darzynkiewicz Z. The concentration-dependent diversity of effects of DNA topoisomerase I and II inhibitors on the cell cycle of HL-60 cells. Exp Cell Res 1991; 195: 485-491.

    Google Scholar 

  48. Hotz MA, 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 15: 237-244.

    Google Scholar 

  49. Del Bino G, Bruno S, Yi PN, Darzynkiewicz Z. Apoptotic cell death triggered by camptothecin or teniposide. The cell cycle specificity and effects of ionizing radiation. Cell Prolif 1992; 25: 537-548.

    Google Scholar 

  50. Hotz MA, Del Bino G, Lassota P, Traganos F, Darzynkiewicz Z. Cytostatic and cytotoxic effects of fostriecin on human promyelocytic HL-60 and lymphocytic MOLT-4 leukemic cells. Cancer Res 1992; 52: 1530-1535.

    Google Scholar 

  51. Pantazis P, Kozielski AJ, Vardeman DM, Petry ER, Giovanella B. Efficacy of camptothecin cogeners in the treatment of human breast carcinoma xenografts. Oncol Res 1994; 5: 273-281.

    Google Scholar 

  52. Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH. The current status of camptothecin analogues as antitumor agents. JNCI 1993; 85: 271-291.

    Google Scholar 

  53. Traganos F. Seiter K, Feldman E, Halicka HD, Darzynkiewicz Z. Induction of apoptosis by camptothecin and topotecan. Ann NY Acad Sci 1996; 803: 101-110.

    Google Scholar 

  54. el-Deiry WS, Tokino T, Velculesco VE et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 813-825.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Cancer Research Institute, New York Medical College Elmsford, USA

    H. D. Halicka, F. Traganos & Z. Darzynkiewicz

  2. Zalmen A. Arlin Cancer Institute, Westchester County Medical Center, Valhalla, USA

    K. Seiter, E. J. Feldman, A. Mittelman & T. Ahmed

Authors
  1. H. D. Halicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Seiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. J. Feldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. Traganos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Mittelman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z. Darzynkiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Z. Darzynkiewicz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Halicka, H.D., Seiter, K., Feldman, E.J. et al. Cell cycle specificity of apoptosis during treatment of leukaemias. Apoptosis 2, 25–39 (1997). https://doi.org/10.1023/A:1026431524236

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026431524236

Search

Navigation