Bone marrow stromal dysfunction in mice administered cytosine arabinoside.

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  • Author(s): Ben-Ishay Z;Ben-Ishay Z; Barak V
  • Source:
    European journal of haematology [Eur J Haematol] 2001 Apr; Vol. 66 (4), pp. 230-7.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Blackwell Country of Publication: England NLM ID: 8703985 Publication Model: Print Cited Medium: Print ISSN: 0902-4441 (Print) Linking ISSN: 09024441 NLM ISO Abbreviation: Eur J Haematol Subsets: MEDLINE
    • Publication Information:
      Publication: <2005->: Oxford : Blackwell
      Original Publication: Copenhagen : Munksgaard, c1987-
    • Subject Terms:
      Bone Marrow Cells/*drug effects ; Cytarabine/*pharmacology ; Stromal Cells/*drug effects; Animals ; Bone Marrow Cells/pathology ; Cell Death/drug effects ; Cell Division/physiology ; Coculture Techniques ; Colony-Forming Units Assay ; Cytarabine/administration & dosage ; Cytokines/analysis ; Cytokines/drug effects ; Cytokines/metabolism ; Dose-Response Relationship, Drug ; Fibroblasts/cytology ; Growth Substances/metabolism ; Hematopoiesis/drug effects ; Injections, Intraperitoneal ; Male ; Mice ; Mice, Inbred C57BL ; Stem Cells/drug effects ; Stromal Cells/metabolism ; Stromal Cells/pathology
    • Abstract:
      Objective: The aim of the study was to investigate ex-vivo the bone marrow (BM) stroma of mice under conditions of low- and high-dose cytosine arabinoside (Ara-C), a cycle-specific drug (S-phase) and to assess possible stromal damage, apart from the killing of hematopoietic cells. Stroma consists of mesenchymal elements generally not in the cell cycle; therefore it could not be a target for the killing effect of Ara- C.
      Materials and Methods: The stromal function was studied by the following: the incidence of stromal stem cells, i.e. CFU-F; formation of stromal layers under growth conditions of long-term culture (LTC) followed by irradiation and overlayering of test cells in contact and non-contact co-cultures; subsequent culture of the test cells in a semi-solid medium to assay the incidence of hyperproliferative potential cells (HPPC); production of GM-CSF, IL-3, IL-4, IL-6 and IFNgamma in the conditioned medium (CM) of confluent stromal layers. All tests and assays were carried out on BM specimens, 1-4 d after Ara-C administration and on controls.
      Results: Low-dose Ara-C induces a marked decrease of CFU-F, compensated by cycle induction of pre-CFU-F, young-type stromal stem cells. High-dose Ara-C causes a CFU-F decrease to almost zero level. The time length to layer confluency is normal after low-dose Ara-C ( approximately 10 d) and prolonged after a high dose ( approximately 30 d). The confluent layers from mice receiving low- or high-dose Ara-C support hematopoiesis adequately. Among the growth factors and cytokines assayed, only IL-6 is detected in CM layers. IL-6 decreases after a low dose of Ara-C and increases after a high dose. The cause of IL-6 fluctuations is yet to be investigated. It is, however, evident that IL-6 is not an essential factor in support of hematopoiesis.
      Conclusions: Taken together, the current study in mice indicates that Ara-C administration, in particular a high dose, induces bone marrow stromal damage and/or disfunction. The long period of time to reach layer confluency after a high Ara-C dose might reflect the in-vivo situation of slow stromal regeneration.
    • Accession Number:
      0 (Cytokines)
      0 (Growth Substances)
      04079A1RDZ (Cytarabine)
    • Publication Date:
      Date Created: 20010531 Date Completed: 20010621 Latest Revision: 20190910
    • Publication Date:
      20231215
    • Accession Number:
      10.1034/j.1600-0609.2001.066004230.x
    • Accession Number:
      11380602