β-内酰胺酶自杀基因系统的构建及其合并放疗治疗肿瘤的研究

Suicide gene therapy is a kind of cancer biotherapy，this method can realize sentinel activation of the antineoplastics, avoiding the systemic side effects, so as to enhance therapeutic effect. Suicide gene therapy combined with radiotherapy can create synergies. In previous work we found that the β-lactamase has high catalytic activity, high plasma stability, low immunogenicity, and used with the prodrug-Cephalosporin-Melphalan has good antineoplastic effect, as lay the foundation of its use for suicide gene therapy. In the present study we will use tumor specific promoter to regulate the transfer of β-lactamase' gene by adenovirus, as can activate β-lactam-based prodrugs to kill tumor cells, and use this suicide gene system with radiotherapy in combination as a new cancer therapy. We plan to investigate the therapeutic effect of the β-lactamase suicide system on tumor in vitro and in vivo in combination with radiotherapy, as will lay the foundation for this system merge radiotherapy as a new strategy for cancer comprehensive therapy.

自杀基因疗法是肿瘤的生物治疗手段之一，该法通过抗肿瘤药的定点释放，提高了治疗效果，多项研究证明该疗法与放疗联用可发挥良好的协同作用。我们在预实验中发现，β-内酰胺酶具有催化活性高，血浆稳定性好，免疫原性低等优点，细胞实验证明该酶与前药头孢-美法仑联用具有良好的抗肿瘤作用，提示该酶是自杀基因疗法的优良候选酶，本课题在此基础上设计应用肿瘤特异性启动子调控腺病毒转染β-内酰胺酶基因，与前药构建自杀基因系统，并与放疗联用治疗肿瘤。本课题拟通过体外细胞模型和体内动物模型研究该系统合并放疗对肿瘤的治疗效果。期望通过一系列临床前研究为β-内酰胺酶自杀基因系统合并放疗作为肿瘤临床治疗新策略提供实验基础。因此，本课题在肿瘤生物治疗和综合治疗方面都具有重要意义。

自杀基因疗法是肿瘤的生物治疗手段之一，该法通过抗肿瘤药的定点释放，提高了治疗效果，多项研究证明该疗法与放疗联用可发挥良好的协同作用。本课题在应用肿瘤特异性启动子调控腺病毒转染β-内酰胺酶基因，与前药构建自杀基因系统，并与放疗联用治疗肿瘤。发现该系统对体内外肿瘤模型都有一定的治疗作用，与放疗联合应用可以提高抑瘤率，表明二者具有一定的协同作用。β-内酰胺酶自杀基因系统与放疗联合作为一种有潜力的“放射基因疗法”对肿瘤治疗具有一定的应用前景。且β-内酰胺酶的底物可以拼合多种抗肿瘤药物作为该系统的前药，其意义在于可以针对不同的肿瘤类型，选择该肿瘤的首选药物与β-内酰胺环拼合，制作有针对性的前药，进一步提高肿瘤治疗的特异性和疗效。因此，本课题在肿瘤生物治疗和综合治疗方面都具有重要意义。