Tumor targeting by doxorubicin-RGD-4C peptide conjugate in an orthotopic mouse hepatoma model.

Vascular targeting is a novel strategy that directs endothelial toxins at tumor vessels expressing specific markers and kills tumor cells by vascular occlusion. Integrin-binding RGD motif has been reported to have a homing property to experimental tumor vasculature. In the present study, we evaluated the effect of vascular targeting by doxorubicin-RGD-4C conjugate in an orthotopic murine hepatoma model. MTT assay showed that dox-RGD-4C conjugates had lower cytotoxicity against MH134 mouse hepatoma cells than free dox. When given intravenously to mice with implanted orthotopic hepatoma, however, the dox-RGD-4C suppressed the growth of hepatoma more effectively than free dox (mean tumor volumes 24 mm(3) vs. 67 mm(3), respectively; p=0.047). Histologic analysis of the hepatoma tissue revealed prominent tumor cell death in the dox-RGD-4C treated group and complete tumor cell necrosis in 40% of cases. Immunochemical staining showed expression of integrin alphav mainly around the tumor nodule. These results show that dox-RGD-4C conjugate has a better antitumor effect in an orthotopic mouse hepatoma model by tumor targeting. Integrin alphav of hepatoma feeding vessels is suggested to be targeted by the dox-RGD-4C conjugate.
AuthorsJin-Wook Kim, Hyo-Suk Lee
JournalInternational journal of molecular medicine (Int J Mol Med) Vol. 14 Issue 4 Pg. 529-35 (Oct 2004) ISSN: 1107-3756 [Print] Greece
PMID15375578 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Integrin alphaV
  • Integrin alphaVbeta3
  • Oligopeptides
  • doxorubucin cysteinyl-aspartyl-cysteinyl-arginyl-glycyl-aspartyl-cycsteinyl-phenylalanyl-cysteine conjugate
  • Doxorubicin
  • Animals
  • Antineoplastic Agents (administration & dosage, chemistry, therapeutic use)
  • Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Disease Models, Animal
  • Doxorubicin (administration & dosage, analogs & derivatives, chemistry, therapeutic use)
  • Immunohistochemistry
  • Integrin alphaV (metabolism)
  • Integrin alphaVbeta3 (metabolism)
  • Male
  • Mice
  • Molecular Structure
  • Neoplasm Transplantation
  • Oligopeptides (administration & dosage, chemistry, therapeutic use)

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