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Bone marrow stromal dysfunction in mice administered cytosine arabinoside
Author(s) -
BenIshay Zina,
Barak Vivian
Publication year - 2001
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1034/j.1600-0609.2001.066004230.x
Subject(s) - stromal cell , bone marrow , haematopoiesis , stem cell , mesenchymal stem cell , cell cycle , ex vivo , stroma , cancer research , andrology , chemistry , microbiology and biotechnology , biology , immunology , medicine , in vitro , pathology , cell , biochemistry , immunohistochemistry
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.