Liu SH, Smyth-Templeton N, Davis AR, Davis EA, Ballian N, Li M, Liu H, Fisher W, Brunicardi FC.

Surgery. 2011 Apr;149(4):484-95. doi: 10.1016/j.surg.2010.11.014. Epub 2011 Feb 5.

Michael E. DeBakey Department of Surgery, Elkins Pancreas Center, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

Copyright © 2011 Mosby, Inc. All rights reserved.

PMID: 21295812 [PubMed – indexed for MEDLINE] PMCID: PMC3072061