Nagy H, Panis Y, Fabre M, Perrin H, Klatzmann D, Houssin D
Laboratoire de Recherche Chirurgicale, Faculté de Médecine Cochin-Port Royal, Paris, France.
Surgery. 1998 Jan;123(1):19-24.
Suicide gene transfer into tumor cells has been proposed for the treatment of various tumors. The most common suicide gene is coded for the herpes simplex type I thymidine kinase (HSV1-TK), which converts nontoxic nucleoside analogs such as ganciclovir into toxic triphosphated compounds. This study evaluated the potential of this treatment for gene therapy of liver tumors.
The sensitivity of different colon carcinoma and hepatoma cell lines to infection by recombinant retroviruses was evaluated. Next, HSV1-TK-expressing derivatives of these cells were generated to analyze their sensitivity to ganciclovir. Finally, these cells were used to generate experimental hepatomas in rats after injection under the liver capsule, and the efficacy and safety of a ganciclovir treatment on tumor growth and survival were evaluated.
All the different cell lines analyzed were sensitive to retroviral-mediated gene transfer, although the susceptibility of individual cell lines to this transfer varied significantly. HSV1-TK derivatives were about 1000-fold more sensitive to the toxic effects of ganciclovir than parental cells. Tumors with HSV1-TK expressing MCA-RH8994 hepatoma cells were then generated. Intraperitoneal injection of 75 mg/kg ganciclovir twice daily for 5 days dramatically reduced the size of HSV1-TK-positive tumors compared with tumor size in untreated control rats (0.4 mm3 versus 65 mm3, p < 0.02). A long-term study demonstrated that this reduction of tumor volume was associated with a significant increase in survival (p < 0.01). Pathologic examination 26 days after the end of ganciclovir injections showed that complete tumor regression was observed in two of five rats. Most important, there was no toxicity associated with these tumors.
In a clinical perspective the good tolerance to treatment and the significant clinical effect observed were encouraging. Gene transfer methods should be established to allow efficient targeting of the tumor cells in vivo.
已提出将自杀基因导入肿瘤细胞用于治疗各种肿瘤。最常见的自杀基因编码单纯疱疹病毒I型胸苷激酶（HSV1-TK），它可将无毒的核苷类似物如更昔洛韦转化为有毒的三磷酸化化合物。本研究评估了这种治疗方法用于肝肿瘤基因治疗的潜力。
评估了不同结肠癌细胞系和肝癌细胞系对重组逆转录病毒感染的敏感性。接下来，产生这些细胞的表达HSV1-TK的衍生物，以分析它们对更昔洛韦的敏感性。最后，将这些细胞在肝包膜下注射后用于在大鼠中产生实验性肝癌，并评估更昔洛韦治疗对肿瘤生长和存活的疗效及安全性。
所有分析的不同细胞系对逆转录病毒介导的基因转移均敏感，尽管各个细胞系对这种转移的易感性差异显著。HSV1-TK衍生物对更昔洛韦毒性作用的敏感性比亲本细胞高约1000倍。然后产生了表达HSV1-TK的MCA-RH8994肝癌细胞的肿瘤。与未治疗的对照大鼠相比，每天两次腹腔注射75mg/kg更昔洛韦，持续5天，显著减小了HSV1-TK阳性肿瘤的大小（0.4mm³对65mm³，p<0.02）。一项长期研究表明，肿瘤体积的减小与存活率的显著提高相关（p<0.01）。更昔洛韦注射结束后26天的病理检查显示，五只大鼠中有两只出现了肿瘤完全消退。最重要的是，这些肿瘤没有相关毒性。
从临床角度来看，观察到的良好的治疗耐受性和显著的临床效果令人鼓舞。应建立基因转移方法，以便在体内有效地靶向肿瘤细胞。
