Gallicchio V S, Hughes N K, Tse K F
Department of Medicine, Lucille P. Markey Cancer Center, University of Kentucky Medical Center, Lexington 40536-0084.
Cytokine. 1993 Jan;5(1):62-71. doi: 10.1016/1043-4666(93)90025-z.
We studied the effect of erythropoietin (EPO) and interleukin 3 (IL-3), either alone or in combination, on the hematopoietic toxicity associated with zidovudine in vivo, as determined by peripheral blood indices, and assay of hematopoietic progenitors, i.e. erythroid (CFU-E/BFU-E), myeloid (CFU-GM) and megakaryocyte (CFU-Meg) from bone marrow and spleen. Previous studies from this laboratory have established that dose escalation of zidovudine to normal mice induced a dose-dependent decrease in hematocrit, white blood cells and platelets with altered populations of marrow and splenic erythroid, myeloid and megakaryocyte progenitors. Daily administration of EPO (50 U/animal, i.p.) and/or IL-3 (5 U/animal, i.p.) was associated with altered peripheral blood indices and progenitor cells. In general, use of EPO and IL-3 alone reduced zidovudine-induced toxicity, notably in erythropoiesis; however, combination EPO/IL-3 was associated with enhanced toxicity with an observed rebound only with the use of < 2.5 mg/ml drug; 2.5 mg/ml drug in the presence of combination EPO/IL-3 accelerated zidovudine-erythroid toxicity. A similar response was noted with circulating platelets and megakaryocyte progenitors. Use of EPO or IL-3, either alone or in combination, failed to reverse zidovudine-induced neutropenia. These studies demonstrate that use of EPO or IL-3, either alone or in combination may serve as an effective adjuvant therapy to modulate the erythroid toxicity associated with lower doses of zidovudine; however, this cytokine therapy was ineffective modulating zidovudine-induced myelosuppression when used in vivo. A reversal in zidovudine-induced myeloid toxicity, therefore may require the use of a myelopoiesis inducing cytokine.
我们研究了促红细胞生成素（EPO）和白细胞介素3（IL-3）单独或联合使用对齐多夫定在体内所致造血毒性的影响，通过外周血指标以及对骨髓和脾脏中造血祖细胞的检测来确定，即红细胞系（CFU-E/BFU-E）、髓系（CFU-GM）和巨核细胞系（CFU-Meg）。本实验室之前的研究表明，将齐多夫定剂量递增给予正常小鼠会导致血细胞比容、白细胞和血小板呈剂量依赖性下降，同时骨髓和脾脏中红细胞系、髓系和巨核细胞祖细胞的数量也会发生改变。每日腹腔注射EPO（50 U/只动物）和/或IL-3（5 U/只动物）会使外周血指标和祖细胞发生改变。总体而言，单独使用EPO和IL-3可降低齐多夫定诱导的毒性，尤其是在红细胞生成方面；然而，EPO/IL-3联合使用却与毒性增强有关，仅在使用浓度低于2.5 mg/ml药物时观察到有反弹现象；在EPO/IL-3联合使用的情况下，2.5 mg/ml药物会加速齐多夫定对红细胞系的毒性。在循环血小板和巨核细胞祖细胞方面也观察到了类似的反应。单独或联合使用EPO或IL-3均未能逆转齐多夫定诱导的中性粒细胞减少。这些研究表明，单独或联合使用EPO或IL-3可作为一种有效的辅助治疗方法，来调节较低剂量齐多夫定相关的红细胞系毒性；然而，这种细胞因子疗法在体内使用时，对调节齐多夫定诱导的骨髓抑制无效。因此，要逆转齐多夫定诱导的髓系毒性，可能需要使用一种诱导髓系生成的细胞因子。
