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Bone marrow stromal dysfunction in mice administered cytosine arabinoside
1Department of Anatomy and Cell Biology, Hebrew University Hadassah Medical School and Immunology Laboratory for Tumor Diagnosis, Oncology Department, Hadassah Medical Center, Jerusalem, Israel.
European Journal of Haematology
|May 31, 2001
Summary
Cytosine arabinoside (Ara-C) chemotherapy can damage bone marrow stroma, particularly at high doses. This study in mice reveals that high-dose Ara-C impairs stromal stem cells and delays stromal regeneration, impacting bone marrow function.
Area of Science:
- Hematology
- Cancer Biology
- Cell Biology
Background:
- Bone marrow (BM) stroma supports hematopoietic cell development.
- Cytosine arabinoside (Ara-C) is a chemotherapy drug targeting S-phase cells.
- The effect of Ara-C on BM stroma, beyond hematopoietic cell killing, is not fully understood.
Purpose of the Study:
- To investigate the ex-vivo effects of low- and high-dose Ara-C on mouse BM stroma.
- To assess potential damage and functional alterations in the BM stroma.
- To evaluate the impact on stromal stem cells and cytokine production.
Main Methods:
- Assessed stromal stem cell incidence (CFU-F) and stromal layer formation in long-term cultures (LTC).
- Co-cultured test cells on stromal layers to evaluate hyperproliferative potential cells (HPPC).
- Measured cytokine production (GM-CSF, IL-3, IL-4, IL-6, IFNγ) in conditioned medium (CM).
Main Results:
- Low-dose Ara-C decreased CFU-F but induced compensatory pre-CFU-F. High-dose Ara-C severely reduced CFU-F.
- Stromal layer confluency was delayed after high-dose Ara-C (approx. 30 days vs. 10 days).
- Interleukin-6 (IL-6) levels fluctuated with Ara-C dose, decreasing with low-dose and increasing with high-dose, but was not essential for hematopoiesis support.
Conclusions:
- Ara-C administration, especially high doses, induces bone marrow stromal damage and dysfunction.
- Prolonged time to stromal confluency after high-dose Ara-C suggests impaired in-vivo stromal regeneration.
- These findings highlight the potential for chemotherapy-induced damage to the supportive BM microenvironment.