Gene Therapy Reverses Cisplatin Resistance in Mouse Xenograft Model

The drugs cause DNA damage, but the inherent resistance of tumors to DNA damage often limits the therapeutic efficacy of these agents. After an initial good response to the drug most cancer patients will relapse with cisplatin-resistant tumors.

Recent studies have shown that this chemoresistance results from an enhanced DNA repair and telomere maintenance response by the Mre11/Rad50/Nbs1 (MRN) enzyme complex. To counter this situation investigators at the University of Pennsylvania School of Medicine (Philadelphia, USA) employed a novel dominant-negative adenoviral vector to deliver a mutant RAD50 gene to human squamous cancer cells growing in tissue culture.

The RAD50 gene normally encodes a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1 that binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination.

The mutant RAS50 gene significantly downregulated MRN expression and markedly disrupted MRN function in the cells. When cisplatin was used to treat the cells following mutant RAD50 therapy, it was evident that the drug produced significant tumor cytotoxicity with a corresponding increase in DNA damage and telomere shortening.

Further results published in the June 1, 2009, issue of the Journal of Clinical Investigation revealed that this combination therapy caused dramatic tumor regression with increased apoptosis in cisplatin-resistant human squamous cell cancer xenografts in nude mice.

The investigators concluded that, "Our findings suggest the use of targeted RAD50 disruption as what we believe to be a novel chemosensitizing approach for cancer therapy in the context of chemoresistance. This strategy is potentially applicable to several types of malignant tumors that demonstrate chemoresistance and may positively impact the treatment of these patients.”

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