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Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents

From the Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network; and Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong.

Address reprint requests to Lillian L. Siu, MD, FRCPC, Princess Margaret Hospital, University Health Network, Suite 5-210, 610 University Ave, Toronto, Ontario, Canada M5G 2M9; email: lillian.siu{at}uhn.on.ca.

Purpose: Molecular targeted agents have been combined with radiotherapy (RT) in recent clinical trials in an effort to optimize the therapeutic index of RT. The appeal of this strategy lies in their potential target specificity and clinically acceptable toxicity.

Design: This article integrates the salient, published research findings into the underlying molecular mechanisms, preclinical efficacy, and clinical applicability of combining RT with molecular targeted agents. These agents include inhibitors of intracellular signal transduction molecules, modulators of apoptosis, inhibitors of cell cycle checkpoints control, antiangiogenic agents, and cyclo-oxygenase-2 inhibitors.

Results: Molecular targeted agents can have direct effects on the cytoprotective and cytotoxic pathways implicated in the cellular response to ionizing radiation (IR). These pathways involve cellular proliferation, DNA repair, cell cycle progression, nuclear transcription, tumor angiogenesis, and prostanoid-associated inflammation. These pathways can also converge to alter RT-induced apoptosis, terminal growth arrest, and reproductive cell death. Pharmacologic modulation of these pathways may potentially enhance tumor response to RT though inhibition of tumor repopulation, improvement of tumor oxygenation, redistribution during the cell cycle, and alteration of intrinsic tumor radiosensitivity.

Conclusion: Combining RT and molecular targeted agents is a rational approach in the treatment of solid tumors. Translation of this approach from promising preclinical data to clinical trials is actively underway.

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