Geissler R G, Muth J, Maurer A, Mentzel U, Mag M, Engels J W, Hoelzer D, Ganser A
Department of Hematology, University of Frankfurt/Main, Germany.
Ann Hematol. 1995 Aug;71(2):89-95. doi: 10.1007/BF01699252.
The hematopoietic failure in the majority of patients with progressive HIV infection is further aggravated by virustatic agents like azidothymidine. As an alternative therapeutic attempt, three derivatives of an antisense oligodeoxynucleotide (ODN) against the splice acceptor site of the tat gene have been shown to inhibit HIV replication in vitro. This study was aimed at examining whether these agents are toxic to the hematopoietic progenitor cells. To this end, bone marrow cells from HIV-positive and healthy persons were depleted from adherent cells to eliminate fibroblasts. In further experiments, the cells were additionally enriched for CD34-positive hematopoietic progenitor cells or were depleted from delta TCS-1-positive T lymphocytes. At concentrations of 1.25-10 microM, the three antisense ODN did not inhibit any erythrocyte or granulocyte-monocyte colony growth from CD34-positive cells, either from the HIV-positive or from the HIV-negative cohort. In contrast to azidothymidine, which served as inhibitory control, a significant increase of colony growth was seen after depletion of fibroblasts, of delta TCS-1-positive cells, or without cell separation. In conclusion, the three oligodeoxynucleotides do not exert any hematotoxic effect but do increase colony formation from low-density bone marrow cells in vitro and could therefore be useful in future clinical studies.
大多数进行性HIV感染患者的造血功能衰竭会因齐多夫定等病毒抑制剂而进一步加重。作为一种替代性治疗尝试，三种针对tat基因剪接受体位点的反义寡脱氧核苷酸（ODN）衍生物已被证明在体外可抑制HIV复制。本研究旨在检验这些药物对造血祖细胞是否有毒性。为此，将HIV阳性和健康人的骨髓细胞去除贴壁细胞以消除成纤维细胞。在进一步的实验中，细胞还被富集了CD34阳性造血祖细胞或去除了δTCS-1阳性T淋巴细胞。在浓度为1.25 - 10微摩尔时，这三种反义ODN均未抑制来自HIV阳性或HIV阴性队列的CD34阳性细胞的任何红细胞或粒细胞 - 单核细胞集落生长。与作为抑制对照的齐多夫定相反，在去除成纤维细胞、δTCS-1阳性细胞后或未进行细胞分离时，集落生长显著增加。总之，这三种寡脱氧核苷酸不会产生任何血液毒性作用，但确实会增加体外低密度骨髓细胞的集落形成，因此可能在未来的临床研究中有用。
