Michael E. DeBakey Department of Surgery, Elkins Pancreas Center, Baylor College of Medicine, Houston, TX 77030, USA.
Surgery. 2011 Apr;149(4):484-95. doi: 10.1016/j.surg.2010.11.014. Epub 2011 Feb 5.
Adenoviral gene therapy has been applied widely for cancer therapy; however, transient gene expression as result of humoral immunoneutralization response to adenovirus limits its effect. The purpose of this study is to determine whether DOTAP:cholesterol liposome could shield adenovirus from neutralizing antibody and permit the use of multiple cycles of intravenous liposome encapsulated serotype 5 adenoviral rat insulin promoter directed thymidine kinase (L-A-5-RIP-TK) with ganciclovir (GCV) to enhance its effect.
The effect of multiple cycles of systemic L-A-5-RIP-TK/GCV therapy was evaluated in grouped PANC-1 SCID mice treated with different numbers of cycles. Humoral immune response to A-5-RIP-TK or L-A-5-RIP-TK was assessed using C57/B6J mice challenged with adenovirus or liposome adenovirus complex.
The minimal residual tumor burden (3.2 ± 0.6 mm(3)) and greatest survival time (153.0 ± 6 days) were obtained in the mice receiving 4 and 3 cycles of therapy, respectively. Toxicity to islet cells associated with RIP-TK/GCV therapy was observed after 4 cycles. DOTAP:chol-encapsulated adenovectors were able to protect adenovectors from the neutralization of high titer of anti-adenoviral antibodies induced by itself.
Multiple treatment cycles of L-A-5-RIP-TK/GCV ablate human PANC-1 cells effectively in SCID mice; however, the mice become diabetic and have substantial mortality after the 4th cycle. Liposome-encapsulated adenovirus is functionally resistant to the neutralizing effects of anti-adenoviral antibodies, suggesting feasibility of multiple cycles of therapy. Liposome encapsulation of the adenovirus may be a promising strategy for repeated delivery of systemic adenoviral gene therapy.
腺病毒基因治疗已广泛应用于癌症治疗；然而，由于对腺病毒的体液免疫中和反应，导致基因表达短暂，限制了其效果。本研究旨在确定 DOTAP：胆固醇脂质体是否可以保护腺病毒免受中和抗体的影响，并允许使用多次静脉内脂质体包裹的血清型 5 腺病毒大鼠胰岛素启动子指导胸苷激酶（L-A-5-RIP-TK）与更昔洛韦（GCV）联合使用，以增强其效果。
通过对接受不同周期治疗的 PANC-1 SCID 小鼠分组，评估多次系统 L-A-5-RIP-TK/GCV 治疗的效果。使用 C57/B6J 小鼠对腺病毒或脂质体腺病毒复合物进行攻击，评估对 A-5-RIP-TK 或 L-A-5-RIP-TK 的体液免疫反应。
接受 4 个和 3 个周期治疗的小鼠的最小残留肿瘤负担（3.2±0.6mm3）和最长生存时间（153.0±6 天）分别为最低和最长。在 4 个周期的 RIP-TK/GCV 治疗后，观察到胰岛细胞与毒性相关。DOTAP：胆固醇包裹的腺病毒载体能够保护腺病毒载体免受自身诱导的高滴度抗腺病毒抗体的中和。
多次 L-A-5-RIP-TK/GCV 治疗周期可有效清除 SCID 小鼠中的人 PANC-1 细胞；然而，在第 4 个周期后，小鼠会发生糖尿病并出现大量死亡。脂质体包裹的腺病毒对中和抗腺病毒抗体的作用具有功能抗性，表明多次治疗周期的可行性。腺病毒的脂质体包封可能是重复全身腺病毒基因治疗的一种有前途的策略。
