Blank Stephanie V, Rubin Stephen C, Coukos George, Amin Kunjlata M, Albelda Steven M, Molnar-Kimber Katherine L
Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Hum Gene Ther. 2002 Mar 20;13(5):627-39. doi: 10.1089/10430340252837224.
Herpes simplex virus type 1 (HSV-1)-based oncolytic treatment is a promising therapeutic approach for malignancy. Recombinant strains of HSV-1 containing mutations in the ICP 34.5 protein have been shown to replicate preferentially in rapidly proliferating malignant cells, resulting in a direct cytolytic effect. We assessed the efficacy of multimutated HSV-1 strains on human cervical cancer, and then used these viruses in combination with radiation therapy, the standard treatment for cervical cancer. The HSV-1 mutants 4009, 7020, 3616, and G207 induced significant lysis of three established human cervical cancer cell lines in vitro in a dose-dependent manner. G207 intratumoral treatment of established subcutaneous C33a tumors in severe combined immunodeficient (SCID) mice significantly reduced tumor burden by 50%. Weekly and triweekly treatments improved efficacy and inhibited flank tumor growth in an administration frequency-dependent manner without toxicity. Combination therapy of a low dose of radiation (1.5 or 3 Gy) and replication-selective HSV mutants infection exhibited increased antitumor effects against cervical cancer cells in vitro. The in vivo effect of G207 combined with low-dose radiation was studied in Me180 xenografts in athymic mice. Treatment of established Me180 tumor nodules with 3 Gy followed by intratumoral G207 administration greatly improved efficacy, resulting in 42% complete eradication of tumor. In conclusion, single and multiple intratumoral injections of G207 significantly reduced tumor burden in xenogeneic models of cervical cancer, and the addition of low-dose radiation further potentiated the effect. These results suggest that replication-selective HSV-1 mutants may be potent oncolytic agents for the treatment of cervical cancer.
基于1型单纯疱疹病毒（HSV-1）的溶瘤治疗是一种很有前景的恶性肿瘤治疗方法。已证明，在ICP 34.5蛋白中含有突变的HSV-1重组菌株可在快速增殖的恶性细胞中优先复制，从而产生直接的细胞溶解作用。我们评估了多突变HSV-1菌株对人宫颈癌的疗效，然后将这些病毒与宫颈癌的标准治疗方法放射疗法联合使用。HSV-1突变体4009、7020、3616和G207在体外以剂量依赖的方式诱导三种已建立的人宫颈癌细胞系发生显著裂解。在严重联合免疫缺陷（SCID）小鼠中，对已建立的皮下C33a肿瘤进行G207瘤内治疗可使肿瘤负荷显著降低50%。每周和每三周进行一次治疗可提高疗效，并以给药频率依赖的方式抑制胁腹肿瘤生长，且无毒性。低剂量辐射（1.5或3 Gy）与复制选择性HSV突变体感染的联合治疗在体外对宫颈癌细胞表现出增强的抗肿瘤作用。在无胸腺小鼠的Me180异种移植模型中研究了G207与低剂量辐射联合使用的体内效果。用3 Gy治疗已建立的Me180肿瘤结节，然后进行瘤内注射G207，可大大提高疗效，使42%的肿瘤完全消除。总之，在宫颈癌异种模型中，单次和多次瘤内注射G207可显著降低肿瘤负荷，添加低剂量辐射可进一步增强效果。这些结果表明，复制选择性HSV-1突变体可能是治疗宫颈癌的有效溶瘤剂。
