title: The cooperative effect of p53 and Rb in local nanotherapy in a rabbit VX2 model of hepatocellular carcinoma.
abstract: OBJECTIVE
  A local nanotherapy (LNT) combining the therapeutic efficacy of trans-arterial embolization, nanoparticles, and p53 gene therapy has been previously presented. The study presented here aimed to further improve the incomplete tumor eradication and limited survival enhancement and to elucidate the molecular mechanism of the LNT.
  
  
  METHODS
  In a tumor-targeting manner, recombinant expressing plasmids harboring wild-type p53 and Rb were either co-transferred or transferred separately to rabbit hepatic VX2 tumors in a poly-L-lysine-modified hydroxyapatite nanoparticle nanoplex and Lipiodol® (Guerbet, Villepinte, France) emulsion via the hepatic artery. Subsequent co-expression of p53 and Rb proteins within the treated tumors was investigated by Western blotting and in situ analysis by laser-scanning confocal microscopy. The therapeutic effect was evaluated by the tumor growth velocity, apoptosis and necrosis rates, their sensitivity to Adriamycin® (ADM), mitomycin C, and fluorouracil, the microvessel density of tumor tissue, and the survival time of animals. Eventually, real-time polymerase chain reaction and enhanced chemiluminescence Western blotting were used to investigate the expressive changes of important genes related to the therapy.
  
  
  RESULTS
  The administration procedure proved safe for the rabbits' liver function, the p53 plus Rb LNT showed significantly better antitumoral effect and lower expression of malignant genes than the p53 or Rb LNT, although no significant difference was observed in animal survival when the p53 plus Rb LNT was compared with the p53 LNT.
  
  
  CONCLUSIONS
  Rb works synergistically with p53 in combined therapy mediated by a poly-L-lysine-modified hydroxyapatite nanoparticle nanoplex to augment the antitumoral effect through the downregulated expression of important genes related to apoptosis, necrosis, growth, differentiation and multidrug resistance of tumor cells. LNT with p53 and Rb is potentially an effective antitumor therapy for hepatocellular carcinoma.
authors.affiliation: Department of general surgery, The second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, Shanxi Province, People's Republic of China.
authors.forename: Shengli
authors.initials: S
authors.lastname: Dong
authors.forename: Qibin
authors.initials: Q
authors.lastname: Tang
authors.forename: Miaoyun
authors.initials: M
authors.lastname: Long
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.forename: Lu
authors.initials: L
authors.lastname: Ye
authors.forename: Gaopeng
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000628:therapy*; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D011817:Rabbits; D016160:Retinoblastoma Protein / Q000235:genetics / Q000627:therapeutic use*; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000627:therapeutic use*
chemical_list: D053769:Nanocapsules; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D004247:DNA
keywords: combined therapy; gene-transfer techniques; nanoparticles; targeting