Gao Jian-Qing, Sugita Toshiki, Kanagawa Naoko, Iida Keisuke, Okada Naoki, Mizuguchi Hiroyuki, Nakayama Takashi, Hayakawa Takao, Yoshie Osamu, Tsutsumi Yasuo, Mayumi Tadanori, Nakagawa Shinsaku
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
Biol Pharm Bull. 2005 Jun;28(6):1066-70. doi: 10.1248/bpb.28.1066.
Considerable attention has recently been paid to the application of chemokines to cancer immunotherapy because of their chemotactic affinity for a variety of immune cells and because several chemokines are strongly angiostatic. In the present study, the recombinant adenovirus vectors encoding chemokine CCL19 or XCL1 in an E1 cassette (AdRGD-mCCL19 and AdRGD-mXCL1) were developed. The constructed fiber-mutant adenovirus vector, which contained the integrin-targeting Arg-Gly-Asp (RGD) sequence in the fiber knob, notably enhanced the transfection efficiency to OV-HM ovarian carcinoma cells compared to that induced by conventional adenovirus vector. The results of an in vitro chemotaxis assay for chemokine-encoding vector demonstrated that both AdRGD-mCCL19 and AdRGD-mXCL1 could induce the migration of cells expressing specific chemokine receptors. Of the two chemokine-encoding vectors evaluated in vivo, AdRGD-mCCL19 showed significant tumor-suppressive activity in B6C3F1 mice via transduction into OV-HM cells, whereas XCL1 did not exhibit any notable anti-tumor effects, suggesting that CCL19 may be a candidate for cancer immunotherapy.
由于趋化因子对多种免疫细胞具有趋化亲和力，且几种趋化因子具有很强的血管生成抑制作用，近年来人们对趋化因子在癌症免疫治疗中的应用给予了相当多的关注。在本研究中，开发了在E1盒中编码趋化因子CCL19或XCL1的重组腺病毒载体（AdRGD-mCCL19和AdRGD-mXCL1）。构建的纤维突变腺病毒载体在纤维结中含有整合素靶向的精氨酸-甘氨酸-天冬氨酸（RGD）序列，与传统腺病毒载体相比，显著提高了对OV-HM卵巢癌细胞的转染效率。对编码趋化因子载体的体外趋化试验结果表明，AdRGD-mCCL19和AdRGD-mXCL1均可诱导表达特定趋化因子受体的细胞迁移。在体内评估的两种编码趋化因子载体中，AdRGD-mCCL19通过转导到OV-HM细胞中，在B6C3F1小鼠中显示出显著的肿瘤抑制活性，而XCL1未表现出任何明显的抗肿瘤作用，这表明CCL19可能是癌症免疫治疗的一个候选者。
