CD自杀基因联合GM-CSF基因治疗的抗肿瘤作用及免疫机理

目的研究自杀基因与粒细胞－巨噬细胞集落刺激因子（ＧＭ－ＣＳＦ）基因联合治疗抗肿瘤作用及免疫机理。方法小鼠皮下接种黑色素瘤Ｂ１６Ｆ１０细胞３天后，分别在肿瘤局部直接注射表达小鼠ＧＭ－ＣＳＦ的重组腺病毒ＡｄＧＭ－ＣＳＦ和表达大肠杆菌胞嘧啶脱氨酶（ＣＤ）基因的腺病毒Ａｄ－ＣＤ，然后连续１０天腹腔注射５氟胞嘧啶（５ＦＣ）（ＡｄＣＤ／５ＦＣ／ＡｄＧＭＣＳＦ组）、单用ＡｄＣＤ／５ＦＣ组、单用ＡｄＧＭ－ＣＳＦ组、注射对照病毒ＡｄｌａｃＺ／５ＦＣ组或ＰＢＳ组。结果与接受ＡｄＣＤ／５ＦＣ、ＡｄＧＭ－ＣＳＦ、ＡｄｌａｃＺ／５ＦＣ或ＰＢＳ治疗的荷瘤小鼠比较，经联合治疗后荷瘤小鼠皮下肿瘤结节的生长明显受到抑制，荷瘤小鼠的存活期明显延长（Ｐ＜０．０１）。经ＡｄＣＤ／５ＦＣ／ＡｄＧＭＣＳＦ联合基因治疗后，肿瘤瘤体内或瘤周有大量树突状细胞、ＣＤ８＋Ｔ细胞浸润，黑色素瘤细胞表达ＭＨＣ－Ⅰ和Ｂ７－１分子明显增加，荷瘤小鼠脾细胞对Ｂ１６Ｆ１０黑色素瘤细胞特异性杀伤功能增强。结论联合应用自杀基因和ＧＭ－ＣＳＦ基因转移可以直接杀伤肿瘤细胞，又可提高机体对肿瘤的免疫应答，两者可协同发挥抗肿瘤作用

Therapeutic effect of combined treatment with CD suicide gene and GM-CSF gene on murine melanoma and its immunological mechanism

Objective To observe the therapeutic effect of adenovirus expressing cytosine deaminase (AdCD) in combination with adenovirus expressing GM CSF (AdGMCSF) followed by administration of a kind of prodrug, 5 fluorocytosine (5FC) on melanoma in mice. Methods Melanoma bearing mice were administered with AdCD/5FC/AdGMCSF, AdCD/5FC, AdGM CSF, control adenovirus AdlacZ/5FC, or PBS. Results The results demonstrated that significant growth inhibition of established tumors and prolongation of survival period were observed in tumor bearing mice after AdCD/5FC/AdGMCSF combined therapy when compared with mice treated with AdCD/5FC, AdGM CSF, AdlacZ/5FC, or PBS ( P <0.01). The activity of cytotoxic T lymphocytes could be induced significantly after the combined therapy. The expression of MHC I and B7 1 molecules on freshly isolated tumor cells after combined therapy increased greatly, and more dendritic cells and CD8 T cells infiltrated into the tumor mass when measured with FACS. Conclusion Our results suggest that combined therapy with suicide gene and GM CSF gene transfer could directly eradicate established tumors and efficiently induce the antitumor immunity of the mice.