Myelosuppressive effects of cytosine arabinoside (Ara-C) on growth factor-dependent human long-term bone marrow cultures (LTBMC).
Freshly isolated human mononuclear cells (5 x 10(6)) were incubated in a Dexter-type long-term bone marrow culture (LTBMC) system to study myelosuppressive effects of cytosine arabinoside (Ara-C) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin 3 (IL-3). Differential counts (dc) of the nonadherent cell (nac) populations, starting with culture initiation, were performed weekly. After one week of simultaneous incubation of LTBMCs with either cytokine (100 ng/ml) and Ara-C (1 microgram/ml), nac numbers were markedly reduced compared to controls. Dc after week 1 of culture demonstrated significant decreases of all myeloid cell fractions except for macrophages, which remained unaffected. Growth factor-dependent LTBMCs exposed to Ara-C showed recovery of promyelocytic, metamyelocytic, and polymorphonuclear cell numbers up to control values (cultures without Ara-C exposure) in weeks 3 to 6. Intriguingly, high-proliferative, early myeloid progenitor cells (myeloblasts) appeared at high rates only in IL-3-dependent LTBMCs with and without Ara-C exposure. Nac numbers in LTBMCs exposed to Ara-C alone declined rapidly; after two weeks of culture only negligible numbers of viable nac were maintained. Plating experiments of nac in the presence of GM-CSF were performed weekly. Granulocyte-macrophage colony-forming units (CFU-GM) yields for nac from IL-3 LTBMCs were consistently higher than those for nac from GM-CSF LTBMCs. Ara-C exposure reduced CFU-GM numbers generated with nac from GM-CSF LTBMCs to 10% of GM-CSF controls (week 1). However, CFU-GM numbers grown with nac from Ara-C exposed GM-CSF-dependent LTBMCs recovered above control levels after week 3.(ABSTRACT TRUNCATED AT 250 WORDS)
Kalla
P
P
Institute for Immunology, University of Mainz, Federal Republic of Germany.
Oster
W
W
Seiler
F R
FR
Rüde
E
E
Krumwieh
D
D
D000328:Adult; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D007700:Kinetics; D008875:Middle Aged
D007377:Interleukin-3; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor