title: Interstitial gene delivery in human xenograft prostate tumors using titanium metal seeds.
abstract: Gene therapy is a promising approach for the treatment of cancers. Strategies for gene vector delivery include systemic and local-regional approaches. Intratumoral delivery of vectors has generally employed direct injections into single or multiple locations throughout the tumor volume. However, this approach leads to nonuniform distributions of reagents within tumors and becomes cumbersome as the required number of injections is increased. We have investigated the effectiveness of an interstitial plasmid gene delivery based on using tiny metallic seeds (GeneSeeds) analogous to technology used for brachytherapy. Feasibility for interstitial use of GeneSeeds was demonstrated expressing reporter plasmids (green fluorescence protein or beta-galactosidase) in human xenograft prostate tumors. Immunohistochemical analysis confirmed effective interstitial delivery, vector expression, and distributions of reporter genes within tumors. Applicability of GeneSeeds for delivery of radiosensitizing cytokines was examined by generating a cytokine [tumor necrosis factor-alpha (TNF-alpha)] expressing vector under the cytomegaloviral promoter and interstitially implanting GeneSeeds with this vector into prostate cancer tumors. TNF-alpha protein expression was observed around the ends of seeds and decreasing in an exponential gradient as a function of distance. The expression of TNF-alpha resulted in tumor growth delay of a human prostate cancer xenograft. These results demonstrate the feasibility of applying interstitial delivery of gene expressing vectors for the treatment of human cancers.
authors.affiliation: Department of Radiation Medicine, Division of Radiation Research, Georgetown University Medical Center, Research Building, Suite E211, Box 571482, Washington, DC 20057-1482, USA. jungm@georgetown.edu
authors.forename: Mira
authors.initials: M
authors.lastname: Jung
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dimtchev
authors.forename: Manny R
authors.initials: MR
authors.lastname: Subramanian
authors.forename: Krishman
authors.initials: K
authors.lastname: Suthanthiran
authors.forename: Anatoly
authors.initials: A
authors.lastname: Dritschilo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques / Q000295:instrumentation*; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000295:instrumentation / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D014025:Titanium / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D014025:Titanium