The decade-long search for agents that increase tumor sensitivities to radiotherapy is now entering the targeted therapies era. With preclinical and early clinical assessments under way to develop agents that effectively target specific tumor gene expression pathways, this innovative technique can help increase radiosensitivity and overcome tumor resistance to radiotherapy.

Candidate radiosensitization pathways currently under investigation include DNA repair pathways and angiogenesis, or the recruitment of new tumor vasculature. But these and other candidate radiosensitizing agents’ effects, once confirmed, will likely hinge on optimal treatment schedules.

A central dilemma for radiation oncology is how to best deliver effective cytotoxic doses of ionizing radiation to tumors while minimizing the irradiation of healthy tissues, which can cause dose-limiting or therapy-interrupting toxicities.1 One solution to this challenge has been improved radiation beam targeting. Conformal three-dimensional radiotherapy and intensity-modulated radiotherapy (IMRT), for example, were developed to allow closer conformation of radiation fields to tumor contours in order to reduce irradiation of healthy non-target tissues. Despite these important advances in conformal radiotherapy, however, treatment with radiation remains a source of significant morbidity among patients with cancer, sometimes limiting the delivery of potentially curative radiation doses to tumors.

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A related and significant challenge for radiotherapy is acquired tumor radioresistance, which leads to local tumor control failure in a large number of patients.2

Both challenges—tumor radioresistance and minimizing irradiation of healthy non-target tissue while maximizing radiation doses delivered to tumors —could be largely resolved if it were possible to administer agents that enhance tumor radiosensitivity; and ideally, this would simultaneously reduce the radiosensitivity of healthy tissue. For patients with malignant glioma, for example, tumor radiosensitizing agents could prolong recurrence-free survival times, and might permit radiation dose de-escalation for prostate tumors, minimizing non-target tissue irradiation.3,4 

A wide range of agents do appear to modulate tissue radiosensitivity. Systemic chemotherapy agents can sometimes increase radiotherapy efficacy, and novel radiosensitizing agents, such as gold nanoparticle-based agents, are also under preclinical development.3,5,6

Preclinical cell line studies suggest that dietary supplements frequently taken by patients with cancer to improve prostate health might differentially increase the radiosensitization of healthy, non-target prostate cells, leading some authors to call for clinicians to discourage patients’ use of these prostate-specific dietary supplements during radiotherapy.7  Research with lab mice suggests that isoflavones from soy plants might facilitate radiation-triggered cell death in tumors while reducing the risk of healthy tissue damage in non-small cell lung cancer.8