Gallicchio V S, Hughes N K, Hulette B C, Noblitt L
Department of Medicine, Lucille P. Markey Cancer Center, University of Kentucky Medical Center, Lexington 40536-0084.
J Leukoc Biol. 1991 Dec;50(6):580-6. doi: 10.1002/jlb.50.6.580.
The drug 3'-azido-3'-deoxythymidine (AZT), a synthetic thymidine analogue, has been used clinically in the management of acquired immune deficiency syndrome (AIDS). The drug is an effective antiviral agent due to its ability to block reverse transcriptase activity. This action of AZT was demonstrated in the Rauscher leukemia virus (RLV)-induced murine erythroleukemia model system. Unfortunately, associated with AZT has been the development of hematopoietic toxicity manifested by anemia, neutropenia, and overall bone marrow suppression. Hematopoietic growth factors (GM-CSF, erythropoietin), cytokines (interleukin-1), and agents known to potentiate hematopoiesis (lithium) have been demonstrated to modulate drug and/or radiation-induced hematopoietic toxicity. We report the results of further studies designed to investigate the ability of GM-CSF, erythropoietin, interleukin-1, and lithium to modulate AZT toxicity on murine hematopoietic granulocyte-macrophage (CFU-GM), megakaryocytic (CFU-Meg), and erythroid (BFU-E) progenitors cultured from bone marrow and spleen cells from mice infected with RLV. Hematopoietic progenitors from either normal or RLV-infected animals when exposed to AZT demonstrated concentration-dependent toxicity and differed for each progenitor with BFU-E being the most sensitive (ID50 concentration, 5 x 10(-9) M) and CFU-GM the least sensitive (ID50 concentration, 5 x 10(-5) M). As has been previously demonstrated using normal murine hematopoietic progenitors, when cultured with RLV-infected marrow or spleen cells, addition of GM-CSF, Meg-CSF or erythropoietin failed to inhibit AZT toxicity in vitro on CFU-GM, CFU-Meg, and BFU-E, respectively. However, in the presence of interleukin-1 (recombinant human IL-1 alpha, 30 ngm) or lithium chloride (ultra-pure, 1.0 mM), AZT toxicity CFU-GM, CFU-Meg, and BFU-E cultured from RLV-infected marrow or spleen cells was reduced. These results further demonstrate interleukin-1 and lithium are effective in modulating the toxic action of AZT on hematopoietic progenitors and that RLV-infected animals serve as a useful viral model system to study the effect of agents capable of modulating hematopoiesis in the presence of the anti-viral drug AZT.
药物3'-叠氮基-3'-脱氧胸苷（AZT）是一种合成的胸苷类似物，已在临床上用于治疗获得性免疫缺陷综合征（艾滋病）。由于其能够阻断逆转录酶活性，该药物是一种有效的抗病毒剂。AZT的这种作用在劳舍尔白血病病毒（RLV）诱导的小鼠红白血病模型系统中得到了证实。不幸的是，与AZT相关的是出现了以贫血、中性粒细胞减少和整体骨髓抑制为表现的造血毒性。造血生长因子（粒细胞-巨噬细胞集落刺激因子、促红细胞生成素）、细胞因子（白细胞介素-1）以及已知能增强造血功能的药物（锂）已被证明可调节药物和/或辐射诱导的造血毒性。我们报告了进一步研究的结果，这些研究旨在调查粒细胞-巨噬细胞集落刺激因子、促红细胞生成素、白细胞介素-1和锂调节AZT对从小鼠骨髓和脾脏细胞培养的小鼠造血粒细胞-巨噬细胞（CFU-GM）、巨核细胞（CFU-Meg）和红系（BFU-E）祖细胞毒性的能力。正常或RLV感染动物的造血祖细胞在暴露于AZT时表现出浓度依赖性毒性，并且每种祖细胞有所不同，其中BFU-E最敏感（半数抑制浓度，5×10⁻⁹ M），CFU-GM最不敏感（半数抑制浓度，5×10⁻⁵ M）。正如先前使用正常小鼠造血祖细胞所证明的那样，当与RLV感染的骨髓或脾脏细胞一起培养时，添加粒细胞-巨噬细胞集落刺激因子、巨核细胞集落刺激因子或促红细胞生成素分别未能在体外抑制AZT对CFU-GM、CFU-Meg和BFU-E的毒性。然而，在存在白细胞介素-1（重组人IL-1α，30 ngm）或氯化锂（超纯，1.0 mM）的情况下，从RLV感染的骨髓或脾脏细胞培养的CFU-GM、CFU-Meg和BFU-E的AZT毒性降低。这些结果进一步证明白细胞介素-1和锂可有效调节AZT对造血祖细胞的毒性作用，并且RLV感染的动物可作为一种有用的病毒模型系统，用于研究在抗病毒药物AZT存在下能够调节造血功能的药物的作用。
