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目的:观察重组人白细胞介素-2(rhIL-2)与阿霉素长循环热敏脂质体(ALTSL)联合靶向治疗荷H22瘤小鼠的协同作用,并探讨其抑瘤作用的机制。方法:以荷H22瘤小鼠的瘤重为指标,评价药物的抑瘤活性。以荷H22瘤小鼠的存活天数计算生命延长率。以乳酸脱氢酶释放法测定NK细胞的杀伤活性。以MTT比色法检测淋巴细胞的转化率。以流式细胞术检测肿瘤细胞的凋亡及p53、Fas、FasL和caspase-3的表达。用RT PCR法测定IL-2mRNA及IL-12mRNA的表达。镜下观察荷H22瘤小鼠肿瘤、心、肝及肾脏组织的病理变化。结果:rhIL2+ALTSL的抑瘤率显著高于单用ALTSL,分别为73.5%和67.0%;ALTSL和rhIL2+ALTSL均可显著延长荷瘤小鼠的存活时间(P<0.05～P<0.01)与对照组和游离阿霉素(FADM)组相比较,ALTSL组NK细胞的杀伤活性显著增加,rhIL2+ALTSL组NK细胞的杀伤活性更高。与FADM组比较,rhIL-2+ALTSL组淋巴细胞的转化率明显提高(P<0.01)。应用ALTSL组和rhIL-2+ALTSL组均可增强脾细胞中IL-2mRNA和IL-12mRNA的表达,但后者的增强作用高于前者。病理切片检查显示,热敏脂质体配合肿瘤局部加热,使肿瘤细胞凝固坏死,联合应用rhIL-2肿瘤组织溶解,细胞破碎,可见大量的淋巴细胞浸润。结论:ALTSL能提高ADM的抑瘤效果,降低ADM心肺的毒性。rhIL-2+ALTSL可诱导肿瘤
OBJECTIVE: To observe the synergistic effect of recombinant human interleukin-2 (rhIL-2) and doxorubicin long-circulating thermosensitive lipids (ALTSL) in targeting H22 tumor-bearing mice and to explore the mechanism of its anti-tumor effect . Methods: The tumor weight of mice bearing H22 tumor was used as an index to evaluate the anti-tumor activity of the drug. The survival rate was calculated as the number of surviving H22 tumor-bearing mice. NK cell killing activity was determined by lactate dehydrogenase release assay. Lymphocyte transformation rate was detected by MTT colorimetry. The apoptosis of tumor cells and the expression of p53, Fas, FasL and caspase-3 were detected by flow cytometry. The expression of IL-2 mRNA and IL-12 mRNA was determined by RT-PCR. Microscopically observe the pathological changes of tumor, heart, liver and kidney in H22 tumor-bearing mice. Results: The inhibitory rate of rhIL2 + ALTSL was significantly higher than that of ALTSL alone (73.5% vs 67.0%, respectively). Both ALTSL and rhIL2 + ALTSL significantly prolonged the survival of tumor-bearing mice (P <0.05 ~ P <0.01) The cytotoxic activity of NK cells in ALTSL group was significantly higher than that in control group and free Doxorubicin (FADM) group, and the cytotoxic activity of NK cells in rhIL2 + ALTSL group was higher. Compared with FADM group, the lymphocyte transformation rate of rhIL-2 + ALTSL group was significantly increased (P <0.01). Application of ALTSL group and rhIL-2 + ALTSL group can enhance the expression of IL-2mRNA and IL-12mRNA in spleen cells, but the latter is stronger than the former. Pathological examination showed that the thermosensitive liposomes combined with the local heating of the tumor caused coagulation and necrosis of the tumor cells. When the rhIL-2 tumor tissue was dissolved and the cells were disrupted, a large amount of lymphocyte infiltration was seen. CONCLUSIONS: ALTSL can enhance the antitumor effect of ADM and reduce the cardiopulmonary toxicity of ADM. rhIL-2 + ALTSL can induce tumors