Modulation of Cytotoxicity and Differentiation-Inducing Potential of Arabinofuranosylcytosine in Myeloid Leukemia Cells by Hematopoietic Cytokines
作者:
BrachMarion A.,
MertelsmannRoland H.,
HerrmannFriedhelm,
期刊:
Cancer Investigation
(Taylor Available online 1993)
卷期:
Volume 11,
issue 2
页码: 198-211
ISSN:0735-7907
年代: 1993
DOI:10.3109/07357909309024840
出版商: Taylor&Francis
数据来源: Taylor
摘要:
Hematopoietic growth factors may be useful in improving the clinical effectiveness of arabinofuranosylcytosine (ara-C). In vitro studies have indicated that interleirkin 3 (IL-3) and, to a lesser extent, granulocyte-macrophage colony-stimulating factor (GM-CSF), but not G-CSF or M-CSF, may be capable of specifically augmenting the abiliry of ara-C to kill leukemic myeloid cells by pharamacological and cyto-kinetic mechanisms including increase of intracellular ara-CTP/dCTP pool ratios and enhanced ara-C DNA incorporation in leukemic blast cells, decrease of IC 90 of ara-C for leukemic colony-forming cells (CFC) as compared with normal CFC growth, and recruitment of quiescent leukemic cells into the cell cycle. In contrast, the combination of ara-C with M-CSF or with the leukemia inhibitory factor (LIF) appears to be useful in overcoming the block in differentiation of leukemic blast, while the effects of GM-CSF and IL-3 on ara-C-induced differentiation appear limited. The combined treatment of human myeloid leukemia cells by ara-C and LIF is associated with down-regulation of c-mycgene expression, transcriptional activation ofjuntfosgene expression, and features of functional differentiation (e.g., the capability to reduce nitroblue tetrazolium, to express lysozyme, or to display differentiation-related surface receptors including C3bi and thec-fmsprotein). On the basis of these in vitro studies first clinical trials are underway that are examining the efficacy of ara-C combinations with these molecules for the treatment of myeloid disorders.
点击下载:
PDF (1175KB)
返 回