第三节　肝胆胰恶性肿瘤的基因治疗

鉴于肝胆胰系统恶性肿瘤恶性程度高,传统疗效差的现状,目前人们正在探索基因治疗的新方法,并在动物模型上取得初步成功,少数成果已运用于临床。 肿瘤的基因治疗方法主要有以下几种:

(一)抑癌基因治疗及其联合化疗

已有证明,多数肿瘤的发生与P53 和P16 抑癌基因的失活有关,恢复抑癌基因的活性是基因治疗的重要方面。 实验显示,通过病毒转染导入正常P53 和P16 抑癌基因,能明显抑制肿瘤细胞生长,并增加肿瘤细胞对化疗药物的敏感性。 因此,抑癌基因治疗联合化疗将来可作为肿瘤的有效治疗方案之一。

(二)自杀基因治疗及其联合放射治疗

所谓“自杀基因”,又称前药转换基因,其表达产物能把无毒性的药物前体转变成细胞毒性药物,从而杀伤肿瘤细胞。 自杀基因治疗又称为病毒导向的酶解药物前体疗法或原药激活疗法,有时亦称为分子化疗,是目前众多基因治疗策略中效果最明显、最有前途的策略之一。 目前应用较多的自杀基因有单纯疱疹病毒胸腺嘧啶核苷激酶(herpes simplex virus thymidinekinase,HSV-tK)基因和大肠埃希菌胞嘧啶脱氨酶(escherichia coli cytosine deaminase,ECCD)基因。 实验显示,导入自杀基因后,肿瘤细胞的死亡率明显增加,呈时间剂量相关性,并与放疗有协同效应,给肿瘤治疗带来新的希望。

(三)抗肿瘤血管生成基因治疗

目前的抗肿瘤血管生成基因治疗,主要是利用反义序列和核酶来抑制血管生成因子的基因表达。国内外文献显示,利用反义序列能明显抑制肿瘤组织的VEGF 基因及蛋白的表达。 因此,抗肿瘤血管生成的基因治疗将是恶性肿瘤治疗的有效辅助手段。

与其他恶性肿瘤的发病一样,肝胆胰系统的肿瘤发生机制十分复杂,是多基因协同作用、多因素参与和多阶段综合发展的结果。 同一肿瘤组织中可存在多个基因的突变,基因突变又可与肿瘤发生的不同阶段相关。 目前,选择单一的抑癌基因治疗、反义基因治疗或自杀基因治疗尚不能取得令人满意的效果。 因此,各种基因治疗方法的联合应用是必然的发展趋势。

(印其友)

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