title: Intratumoral versus intravenous gene therapy using a transcriptionally targeted viral vector in an orthotopic hepatocellular carcinoma rat model.
abstract: OBJECTIVE
  To evaluate the feasibility of intratumoral delivery of adenoviral vector carrying a bidirectional two-step transcriptional amplification (TSTA) system to amplify transcriptional strength of cancer-specific Survivin promoter in a hepatocellular carcinoma model.
  
  
  METHODS
  MCA-RH7777 cells were implanted in rat liver, and tumor formation was confirmed with [(18)F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). The adenoviral vector studied had Survivin promoter driving a therapeutic gene (tumor necrosis factor-α-related apoptosis-inducing ligand [TRAIL]) and a reporter gene (firefly luciferase [FL]; Ad-pSurvivin-TSTA-TRAIL-FL). Tumor-bearing rats were administered Ad-pSurvivin-TSTA-TRAIL-FL intravenously (n = 7) or intratumorally (n = 8). For control groups, adenovirus FL under cytomegalovirus (CMV) promoter (Ad-pCMV-FL) was administered intravenously (n = 3) or intratumorally (n = 3). One day after delivery, bioluminescence imaging was performed to evaluate transduction. At 4 and 7 days after delivery, 18F-FDG-PET was performed to evaluate therapeutic efficacy.
  
  
  RESULTS
  With intravenous delivery, Ad-pSurvivin-TSTA-TRAIL-FL showed no measurable liver tumor FL signal on day 1 after delivery, but showed better therapeutic efficacy than Ad-pCMV-FL on day 7 (PET tumor/liver ratio, 3.5 ± 0.58 vs 6.0 ± 0.71; P = .02). With intratumoral delivery, Ad-pSurvivin-TSTA-TRAIL-FL showed positive FL signal from all tumors and better therapeutic efficacy than Ad-pCMV-FL on day 7 (2.4 ± 0.50 vs 5.4 ± 0.78; P = .01). In addition, intratumoral delivery of Ad-pSurvivin-TSTA-TRAIL-FL demonstrated significant decrease in tumoral viability compared with intravenous delivery (2.4 ± 0.50 vs 3.5 ± 0.58; P = .03).
  
  
  CONCLUSIONS
  Intratumoral delivery of a transcriptionally targeted therapeutic vector for amplifying tumor-specific effect demonstrated better transduction efficiency and therapeutic efficacy for liver cancer than systemic delivery, and may lead to improved therapeutic outcome for future clinical practice.
authors.affiliation: Division of Interventional Radiology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Kim
authors.forename: Byeong-Cheol
authors.initials: BC
authors.lastname: Ahn
authors.forename: John A
authors.initials: JA
authors.lastname: Ronald
authors.forename: Regina
authors.initials: R
authors.lastname: Katzenberg
authors.forename: Abhinav
authors.initials: A
authors.lastname: Singh
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Paulmurugan
authors.forename: Sunetra
authors.initials: S
authors.lastname: Ray
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.forename: Lawrence V
authors.initials: LV
authors.lastname: Hofmann
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D005240:Feasibility Studies; D019788:Fluorodeoxyglucose F18; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D015552:Injections, Intralesional; D007275:Injections, Intravenous; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D008163:Luminescent Measurements; D049268:Positron-Emission Tomography; D011401:Promoter Regions, Genetic; D019275:Radiopharmaceuticals; D051381:Rats; D011915:Rats, Inbred BUF; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic; D014161:Transduction, Genetic
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D019275:Radiopharmaceuticals; D053221:TNF-Related Apoptosis-Inducing Ligand; D019788:Fluorodeoxyglucose F18; D049409:Luciferases, Firefly