title: Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Michael E. DeBakey Department of Surgery, Elkins Pancreas Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shi-He
authors.initials: SH
authors.lastname: Liu
authors.forename: Nancy
authors.initials: N
authors.lastname: Smyth-Templeton
authors.forename: Alan R
authors.initials: AR
authors.lastname: Davis
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Davis
authors.forename: Nikiforos
authors.initials: N
authors.lastname: Ballian
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: William
authors.initials: W
authors.lastname: Fisher
authors.forename: F Charles
authors.initials: FC
authors.lastname: Brunicardi
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage; D017209:Apoptosis; D002277:Carcinoma / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D003920:Diabetes Mellitus / Q000209:etiology / Q000473:pathology; D015774:Ganciclovir / Q000008:administration & dosage; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D056724:Immunity, Humoral; D007515:Islets of Langerhans / Q000473:pathology; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy*; D011401:Promoter Regions, Genetic; D051381:Rats; D013937:Thymidine Kinase / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; D018398:Homeodomain Proteins; D008081:Liposomes; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D013937:Thymidine Kinase; D015774:Ganciclovir