June 2, 2009 Researchers have now identified a way to enhance the in vitro anticancer effects of the commonly used platinum-based drug cisplatin and hope that it might be possible to translate these data into the development of a clinical strategy to enhance the anti-cancer effects of platinum-based drugs.
Daqing Li and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have identified in vitro and in mice a way to enhance the anticancer effects of the commonly used platinum-based drug cisplatin.
For many forms of cancer, including testicular, ovarian, and lung cancer, platinum-based drugs that cause DNA damage are the first choice treatment. However, the utility of these drugs is often limited by the enhanced ability of cancer cells to repair their DNA. As the MRN protein complex, which contains the protein RAD50, has a key role in the molecular pathways that control DNA repair in human cells, Li and colleagues set out to test the hypothesis that attenuating the function of the MRN protein complex might sensitize cancer cells to the effects of cisplatin.
The hypothesis was proven using a genetic approach to disrupt MRN function. Specifically, human squamous cell carcinoma cells resistant to the toxic effects of cisplatin became sensitive to the drug when it was combined with an adenoviral vector that drove expression of a dominant-negative RAD50 protein in the cancer cells. Importantly, the combination therapy had potent anti–cancer cell effects in vitro and in mice transplanted with human squamous cell carcinoma cells resistant to cisplatin. The authors therefore hope that it might be possible to develop a clinical strategy to attenuate MRN function and enhance the anticancer effects of platinum-based drugs.
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- Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy. Journal of Clinical Investigation, June 2009
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