Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / immunology
  • Animals
  • Antibodies, Neutralizing / blood
  • Antiviral Agents / administration & dosage
  • Apoptosis
  • Carcinoma / metabolism
  • Carcinoma / therapy*
  • Cell Line, Tumor
  • Diabetes Mellitus / etiology
  • Diabetes Mellitus / pathology
  • Ganciclovir / administration & dosage
  • Genetic Therapy / adverse effects
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunity, Humoral
  • Islets of Langerhans / pathology
  • Liposomes / administration & dosage
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, SCID
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / therapy*
  • Promoter Regions, Genetic
  • Rats
  • Thymidine Kinase / administration & dosage
  • Thymidine Kinase / genetics*
  • Thymidine Kinase / metabolism
  • Trans-Activators / metabolism
  • Tumor Burden
  • Xenograft Model Antitumor Assays


  • Antibodies, Neutralizing
  • Antiviral Agents
  • Homeodomain Proteins
  • Liposomes
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Thymidine Kinase
  • Ganciclovir