Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA.

Fanconi anemia (FA) is a rare genetic disorder characterized by bone-marrow failure and cellular hypersensitivity to crosslinking agents, including cisplatin. Here, we studied the use of the FA pathway as a possible target for cancer gene therapy with the aim to sensitize tumor cells for cisplatin by interfering with the ...
FA pathway. As proof-of-principle, FA and non-FA lymphoblast-derived tumors were grown subcutaneously in scid mice and treated with two different concentrations of cisplatin. As predicted, the antitumor response was considerably improved in FA tumors. An adenoviral vector encoding a dominant-negative form of FANCA, FANCA600DN, was generated that interfered with endogenous FANCA-FANCG interaction resulting in the disruption of the FA pathway as illustrated by disturbed FANCD2 monoubiquitination. A panel of cell lines, including non-small-cell lung cancer cells, could be sensitized approximately two- to three-fold for cisplatin after Ad.CMV.FANCA600DN infection that may increase upon enhanced infection efficiency. In conclusion, targeting the FA pathway may provide a novel strategy for the sensitization of solid tumors for cisplatin and, in addition, provides a tool for examining the role of the FA pathway in determining chemoresistance in different tumor types.
Mesh Terms:
Adenoviridae, Animals, Antineoplastic Agents, Cell Extracts, Cell Line, Tumor, Cisplatin, DNA-Binding Proteins, Drug Resistance, Neoplasm, Fanconi Anemia, Fanconi Anemia Complementation Group A Protein, Fanconi Anemia Complementation Group D2 Protein, Fanconi Anemia Complementation Group G Protein, Gene Expression, Gene Therapy, Genetic Vectors, Humans, Immunoprecipitation, Mice, Neoplasms, Nuclear Proteins, Xenograft Model Antitumor Assays
Cancer Gene Ther.
Date: Aug. 01, 2004
Download Curated Data For This Publication
Switch View:
  • Interactions 1