[重组人白细胞介素-2与阿霉素长循环热敏脂质体在肿瘤靶向治疗中的协同作用]

[Synergistic role between rhIL-2 and adriamycin long circulating temperature-sensitive liposome in targeting therapy on tumor].

作者信息

Dong Lan-feng, Mei He-shan, Song Shu-xia, Lu Zhan-jun

机构信息

Department of Laboratory Animal Sciences, Hebei Medical University, Shijiazhuang 050017, China.

出版信息

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2005 May;21(3):296-300.

PMID:15862144

Abstract

AIM

To observe the synergistic role between rhIL-2 and adriamycin long circulating temperature-sensitive liposome (ALTSL) in targeting therapy of H22 tumor-bearing mice and explore their anti-tumor mechanism.

METHODS

The antitumor activity was evaluated by using the tumor's weight as an index. The prolongation rate of mouse life was calculated according to the survival time of the tumor-bearing mice. The killer activity of NK cells and the lymphocyte transformation rate were detected by the LDH and MTT colorimetry, respectively. The apoptosis of tumor cells and the expression of p53, Fas, Fas-L and Caspase-3 were analyzed by flow cytometry (FCM). The expression of IL-2 mRNA and IL-12 mRNA in splenocytes was determined by RT-PCR. The pathologic changes of tumor, heart, liver and kidney tissues of the tumor-bearing mice were observed under light microscope.

RESULTS

The tumoristatic rate of rhIL-2+ALTSL (73.5%) was higher than that of adriamycin liposome (ADML) group (67.0%). The survival time of tumor-bearing mice in ALTSL and rhIL-2+ALTSL groups was significantly extended as compared with the NS group (treated with normal saline) and the free ADM group (P <0.01 or P <0.05). The killer activities of NK cells of ALTSL group and rhIL-2+ALTSL group were higher than those of the NS and free ADM groups, and was highest in rhIL-2+ALTSL group. The lymphocyte transformation rate of ALTSL+rhIL-2 group markedly increased ( P <0.01) as compared with the free ADM group. The result of RT-PCR indicated that the expression of IL-2 mRNA and IL-12 mRNA in splenocytes in the adriamycin long circulating liposome (ALCL) group was significantly higher than that in the free ADM group. The enhancement of rhIL-2+ALTSL on expression of IL-2 mRNA and IL-12 mRNA was much stronger than that of ALTSL alone. The pathological examination indicated that in rhIL-2+ALTSL group, the tumor cells were mostly destroyed, and a large amount of lymphocytes and monocytes were found in tumor tissue.

CONCLUSION

ALTSL can increase the anti-tumor effect and decreased the side-effects (such as the cytotoxicity) of ADM. rhIL-2+ALTSL can induce the apoptosis of tumor cells and enhance killer activities of T cells and NK cells. rhIL-2 and ALTSL can synergistically play the antitumor effect.

摘要

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）在荷H22肿瘤小鼠靶向治疗中的协同作用，并探讨其抗肿瘤机制。

方法

以肿瘤重量为指标评价抗肿瘤活性。根据荷瘤小鼠的生存时间计算小鼠生命延长率。分别采用乳酸脱氢酶（LDH）法和噻唑蓝（MTT）比色法检测自然杀伤细胞（NK细胞）杀伤活性和淋巴细胞转化率。采用流式细胞术（FCM）分析肿瘤细胞凋亡及p53、Fas、Fas-L和Caspase-3的表达。采用逆转录聚合酶链反应（RT-PCR）检测脾细胞中IL-2 mRNA和IL-12 mRNA的表达。光镜下观察荷瘤小鼠肿瘤、心脏、肝脏和肾脏组织的病理变化。

结果

rhIL-2+ALTSL组抑瘤率（73.5%）高于阿霉素脂质体（ADML）组（67.0%）。与生理盐水组（NS组）和游离阿霉素（ADM）组相比，ALTSL组和rhIL-2+ALTSL组荷瘤小鼠的生存时间显著延长（P<0.01或P<0.05）。ALTSL组和rhIL-2+ALTSL组NK细胞杀伤活性高于NS组和游离ADM组，rhIL-2+ALTSL组最高。与游离ADM组相比，ALTSL+rhIL-2组淋巴细胞转化率明显升高（P<0.01）。RT-PCR结果显示，阿霉素长循环脂质体（ALCL）组脾细胞中IL-2 mRNA和IL-12 mRNA的表达明显高于游离ADM组。rhIL-2+ALTSL对IL-2 mRNA和IL-12 mRNA表达的增强作用明显强于单独的ALTSL。病理检查显示，rhIL-2+ALTSL组肿瘤细胞大多被破坏，肿瘤组织中有大量淋巴细胞和单核细胞。