摘要
为了增强化疗药物对白血病细胞的杀伤效应 ,而又最大限度地减少化疗的毒副作用 ,本研究探讨了低剂量照射增强Ara C抗白血病的作用及其作用机理。实验用小鼠急性淋巴细胞性白血病模型 (L615 )进行 ,先确定低剂量全身照射与小剂量Ara C最佳联合治疗方案 ;在此基础上观察该方案对血液系统的毒副作用 ,并从骨髓病理形态学的动态观察、残留白血病细胞检测、骨髓基质细胞GM CSF表达 (免疫酶标法 )、骨髓条件培养上清液GM CSF水平 (微孔滤膜免疫金银染色法 )等探讨其疗效机理。研究结果表明 ,小鼠于接种白血病细胞后第 4天给予 30 0cGy全身照射后 ,间隔 1,2或 3天连续 3天给予 30mg kgAra C ,有 5 8% - 72 %的动物存活 >30天 ,其中 17%的小鼠获得治愈 ,30天内因白血病死亡小鼠的存活时间也比单纯照射和单纯Ara C组明显延长 (P <0 .0 5 )。该治疗方案对外周血白细胞数和骨髓有核细胞数有一过性减少 ,但恢复较快。骨髓病理形态学观察发现 ,30 0cGy照射后小鼠骨髓轻度抑制 ,血窦扩张充血 ;骨髓基质细胞GM CSF表达高于正常 ;骨髓细胞条件培养液的GM CSF水平也高于正常。由此可见 ,低剂量照射与小剂量Ara C联合具有明显的协同作用 ,其机理可能与低剂量照射增加骨髓血窦的通透性 ,诱导骨髓基质细胞产生细胞因子 。
For effectively enhancing the anti-leukemia effect of chemotherapeutic agents, and meanwhile decreasing the side effect of these agents, the study has been made to explore the synergistic effect of low dose irradiation (LDI) combined with Ara-C on murine leukemia and its mechanism. Firstly, an optimal scheme of low dose total body irradiation combined with Ara-C was established in L615 leukemia (T lymphocytic leukemia) mouse model. The machanism of the enhancing effect was explored by patho-morphological observation, examination of residual leukemia cells, the expression of GM-CSF on the surface of marrow stromal cells and in the bone marrow cultural supernatants. The results showed that the optimal scheme was 300 cGy irradiation at 4 days after inoculation of leukemic cells followed by Ara-C 30 mg/kg ×3 days in an interval of 1, 2 or 3 days after irradiation. The mean survival time of the L615 leukemia mice in LDI+Ara-C combined treatment groups was longer than that of control groups. The percentage of long-term survival mice (>30 days) was the highest (58%-72%), too. 17% of the mice were be cured. The numbers of blood leukocytes and marrow nucleated cells were transiently decreased in combined treatment group, and then recovered rapidly. Slight myelosuppression and marrow sinus dilation and congestion were seen after 300 cGy irradiation. The expression of GM-CSF either on the stromal cells or in marrow cultural supernatant after irradiation increased strikingly (P<0.05). Therefore, LDI combined with Ara-C possesses synergistic effect. The mechanism is possibly related to three facts: LDI could increase the permeability of bone marrow sinus; LDI could promote marrow stromal cells to produce some cytokines (such as GM-CSF, etc.) which drive leukemia cells into cell cycle to make the cells more sensitive to chemotherapeutic agents; and LDI could augment Ara-C-induced cytotoxicity through the mechanism of apoptosis.
出处
《中国实验血液学杂志》
CAS
CSCD
2001年第1期62-66,共5页
Journal of Experimental Hematology
关键词
低剂量照射
化疗药物
ARA-C
小鼠白血病
协同作用
low dose irradiation chemotherapeutic agent Ara-C mouse leukemia synergistic effect
