Gene therapy of salivary gland carcinoma with virus vector

唾液腺癌的复发和局部及全身转移是很常见的，这种情况通常对化疗和放疗是难治的。为了治疗这些晚期病例，需要新的治疗方法。基因治疗是治疗这些病例的方法之一。虽然用于基因治疗的病毒通常经过基因修饰，以传递治疗性转基因并预防病毒感染，但具有复制能力的1型单纯疱疹病毒（HSV-1）也可用于癌症治疗，因为HSV-1在癌细胞内的复制可导致其破坏。hrR3病毒在HSV-1 ICP6基因中有lacZ插入。ICP6基因编码HSV核糖核苷酸还原酶的大亚基，其表达的缺失降低了hrR3在非分裂细胞中复制的能力，并增加了肿瘤细胞裂解的特异性。为了获得更有效的治疗唾液腺癌的HSV-1突变体，我们在Vero细胞和人唾液腺腺癌HSY细胞中反复传代hrR3，选择了一个融合诱导突变体hrR3f。当HSY细胞在低MOI输入下被hrR3或hrR3f感染时，hrR3f比hrR3更有效地使肿瘤细胞退化，因为hrR3f感染细胞附近的细胞容易参与多核细胞的形成。利用HSY细胞在裸鼠胰腺皮下组织中建立异种移植肿瘤。在裸鼠模型中，多次重复经皮注射hrR3f病毒，共三次剂量的方案耐受性良好，并发现完全抑制肿瘤生长。这些研究证明了hsv -1突变体抑制唾液腺癌的能力。

Recurrence and regional and systemic metastases of salivary gland carcinoma occur frequently, and this condition is generally refractory to chemotherapy and radiotherapy. In order to treat these advanced cases, novel therapy is required. Gene therapy is one of the approaches for the treatment of these cases. Although viruses used for gene therapy are usually genetically modified to deliver therapeutic transgenes and prevent viral infection, replication-competent herpes simplex virus type 1 (HSV-1) may be also used for cancer therapy because replication of HSV-1 within cancer cells can result in their destruction.hrR3 virus has a lacZ insertion into the HSV-1 ICP6 gene. The ICP6 gene encodes the large subunit of HSV ribonucleotide reductase, and loss of its expression decreases the ability of the hrR3 to replicate in nondividing cells and increases specificity for tumor cell lysis. To obtain more effective HSV-1 mutant for the treatment of salivary gland carcinoma, we selected a fusion-inducing mutant hrR3f after repeated passages of hrR3 in Vero cells and human salivary gland adenocarcinoma HSY cells. When HSY cells were infected with hrR3 or hrR3f at a low input MOI, hrR3f could degenerate tumor cells more efficiently as compare with hrR3, because cells adjacent to hrR3f-infected cells were readily involved in polykaryocyte formation. Xenograft tumors were established in the subcutaneous tissue of the franks of nude mice, using HSY cells. A schedule consisting of multiple repeated percutaneous injection of hrR3f virus, to a total of three doses, was well tolerated and found inhibit tumor growth completely in the nude mouse model.These studies have demonstrated the ability of theHSV-1 mutants to inhibit salivary gland carcinomas.