Bone marrow stromal dysfunction in mice administered cytosine arabinoside

Z Ben‐Ishay, V Barak - European journal of haematology, 2001 - Wiley Online Library
Z Ben‐Ishay, V Barak
European journal of haematology, 2001Wiley Online Library
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, ie …
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 IFNγ 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 (∼10 d) and prolonged after a high dose (∼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.
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