Despite the clear evidence that hypoxia is deleterious for achieving local tumor control and better survival after radiotherapy, there is no established method for reducing or eliminating it. In PNAS, Benej et al.(1) describe a class of hypoxic radiosensitizers that decreases hypoxia by blocking mitochondrial complex 1 to inhibit oxygen consumption rate. The lead compound is papavarine, a drug approved by the Food and Drug Administration to treat erectile dysfunction and vasospasm. Importantly, the activity of the drug in inhibiting complex 1 is distinct from the phosphodiesterase activity associated with vasodilation. This feature permitted the development of derivatives that maintain the mitochondrial activity but lack the phosphodiesterase activity. It is well established that hypoxic cells are two to three times more resistant to radiation than aerobic cells (2). Theoretically, therefore, hypoxia could be a cause for treatment failure after radiotherapy, because the radiation dose required to sterilize all tumor cells would exceed the normal tissue tolerance dose. In 1955, Thomlinson and Gray (3) published the first paper to suggest that hypoxia could be a cause for radioresistance in human tumors. This landmark paper clearly demonstrated that tumor cords in lung rarely became larger than 180 μm, regardless of the size of any tumor lesion. Beyond 180 μm from the vasculature, the tissue was necrotic. Thomlinson and Gray modeled oxygen transport using available laboratory data and, from that, speculated that cells at the border between the feeding vasculature and the necrosis would be radiobiologically hypoxic [partial oxygen pressure (pO2)< 10 mmHg]. Following this prediction, many clinical studies have reported that human tumors are hypoxic and that hypoxia reduces the likelihood for local tumor control after radiotherapy or chemoradiotherapy (4). The first tests of associations between hypoxia and radiotherapy or radiochemotherapy outcome used invasive polarographic electrodes. As an example, in a metaanalysis of head and neck cancer patients treated with radiotherapy or chemoradiotherapy, hypoxic fraction was independently associated with survival (5).

A multitude of studies at the preclinical level and in human clinical trials evaluated dozens of putative methods to reduce or eliminate hypoxia during radiotherapy (6). In an extensive review of the clinical literature, Overgaard and Horsman reported a metaanalysis of 83 randomized trials involving over 10,000 patients (6). The common goal was to improve local tumor control and survival after radiotherapy or radiochemotherapy by reducing hypoxia. The clinical trials focused on three approaches:(i) increasing oxygen delivery,(ii) using drugs that mimic the radiosensitizing properties of oxygen, or (iii) using drugs that selectively kill hypoxic cells. The overall benefit of these strategies was not significant in most trials. The most convincing result came from metaanalysis evidence that reduction in hypoxia was beneficial after radiotherapy in head and neck cancer (6, 7). The key question, then, is why the randomized trials failed overall to demonstrate an impact on improving tumor control after radiotherapy. Many of the trials were underpowered, which contributed to lack of potential significance (6, 7). However, there is no doubt that three other mitigating issues contributed to lack of success: