Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models
Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models
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DOI：
10.1158/1078-0432.ccr-07-4732
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发表时间：
2008-06-15
影响因子：
11.5
通讯作者：
Jooss, Karin
中科院分区：
文献类型：
--
作者：
Ganesh, Shanthi;Gonzalez-Edick, Melissa;Jooss, Karin
目的：评价透明质酸酶与溶瘤腺病毒的共传递，以确定其是否改善病毒在肿瘤中的传播，从而在肿瘤模型中产生更大的整体抗肿瘤效果。实验设计：将表达绿色荧光蛋白(GFP)的腺病毒在肿瘤模型中提供最佳转导效率和扩散的最佳剂量的透明质酸酶与肿瘤溶解病毒联合治疗，以确定联合治疗是否导致抗肿瘤效果的提高。结果：在注射腺病毒Ad5/35GFP和最佳剂量透明质酸酶(50U)的小鼠中，与单纯注射病毒的动物相比，表达GFP的细胞数量显著增加(P<；0.0001)。当溶瘤腺病毒Ad50OV或Ad5/35OV(OV-5或OV5T35H)与50U透明质酸酶共注射时，肿瘤进展显著延迟，这导致荷瘤小鼠的平均生存时间显著延长(P<；0.0001)。此外，联合应用Ad5/35OV和透明质酸酶的小鼠抗肿瘤效果最好。重要的是，联合治疗并没有增加肿瘤的转移潜力。结论：联合注射溶瘤腺病毒和透明质酸酶可显著提高荷高侵袭性肿瘤小鼠的抗肿瘤活性和总存活率，这可能是一种有效的治疗癌症患者的新方法。
Purpose: Evaluate the codelivery of hyaluronidase enzyme with oncolytic adenoviruses to determine whether it improves the spread of the virus throughout tumors, thereby leading to a greater overall antitumor efficacy in tumor models.Experimental Design: The optimal dose of hyaluronidase that provided best transduction efficiency and spread of a green fluorescent protein (GFP)-expressing adenovirus within tumors was combined with oncolytic viruses in tumor models to determine whether the combination treatment results in an improvement of antitumor efficacy.Results: In mice injected with the adenovirus Ad5/35GFP and an optimal dose of hyaluronidase (50 U), a significant increase in the number of GFP-expressing cells was observed when compared with animals injected with virus only (P < 0.0001). When the oncolytic adenoviruses Ad5OV or Ad5/35 OV (OV-5 or OV5T35H) were codelivered with 50 U of hyaluronidase, a significant delay in tumor progression was observed, which translated into a significant increase in the mean survival time of tumor-bearing mice compared with either of the monotherapy-treated groups (P < 0.0001). Furthermore, the mice that received the combination of Ad5/35 OV and hyaluronidase showed the best antitumor efficacy. Importantly, the combination treatment did not increase the metastatic potential of the tumors. Lastly, the increase in virus potency observed in animals injected with both enzyme and virus correlated with enhanced virus spread throughout tumors.Conclusion: Antitumor activity and overall survival of mice bearing highly aggressive tumors are significantly improved by codelivery of oncolytic adenoviruses and hyaluronidase when compared with either of the monotherapy-treated groups, and it may prove to be a potent and novel approach to treating patients with cancer.