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A Potential Solution for Eliminating Hypoxia As a Cause for Radioresistance Mark W

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A Potential Solution for Eliminating Hypoxia As a Cause for Radioresistance Mark W COMMENTARY COMMENTARY A potential solution for eliminating hypoxia as a cause for radioresistance Mark W. Dewhirsta,1 Despite the clear evidence that hypoxia is deleterious hypoxic fraction was independently associated with for achieving local tumor control and better survival survival (5). after radiotherapy, there is no established method for A multitude of studies at the preclinical level and reducing or eliminating it. In PNAS, Benej et al. (1) in human clinical trials evaluated dozens of putative describe a class of hypoxic radiosensitizers that de- methods to reduce or eliminate hypoxia during creases hypoxia by blocking mitochondrial complex radiotherapy (6). In an extensive review of the clinical 1 to inhibit oxygen consumption rate. The lead com- literature, Overgaard and Horsman reported a meta- pound is papavarine, a drug approved by the Food analysis of 83 randomized trials involving over 10,000 and Drug Administration to treat erectile dysfunction patients (6). The common goal was to improve local and vasospasm. Importantly, the activity of the drug tumor control and survival after radiotherapy or radio- in inhibiting complex 1 is distinct from the phospho- chemotherapy by reducing hypoxia. The clinical trials diesterase activity associated with vasodilation. This focused on three approaches: (i) increasing oxygen feature permitted the development of derivatives delivery, (ii) using drugs that mimic the radiosensitiz- that maintain the mitochondrial activity but lack the ing properties of oxygen, or (iii) using drugs that se- phosphodiesterase activity. lectively kill hypoxic cells. The overall benefit of these It is well established that hypoxic cells are two to strategies was not significant in most trials. The most three times more resistant to radiation than aerobic convincing result came from metaanalysis evidence cells (2). Theoretically, therefore, hypoxia could be a that reduction in hypoxia was beneficial after radio- cause for treatment failure after radiotherapy, be- therapy in head and neck cancer (6, 7). cause the radiation dose required to sterilize all tu- The key question, then, is why the randomized mor cells would exceed the normal tissue tolerance trials failed overall to demonstrate an impact on dose. In 1955, Thomlinson and Gray (3) published improving tumor control after radiotherapy. Many of the first paper to suggest that hypoxia could be a the trials were underpowered, which contributed to cause for radioresistance in human tumors. This lack of potential significance (6, 7). However, there is landmark paper clearly demonstrated that tumor no doubt that three other mitigating issues contrib- μ cords in lung rarely became larger than 180 m, re- uted to lack of success: gardless of the size of any tumor lesion. Beyond 180 μm from the vasculature, the tissue was necrotic. i) Not all human cancers are hypoxic. Extensive Thomlinson and Gray modeled oxygen transport us- studies using oxygen electrodes and imaging ing available laboratory data and, from that, specu- methods show that the extent of hypoxia varies lated that cells at the border between the feeding widely and that not all human tumors are hypoxic vasculature and the necrosis would be radiobiolog- (4). Design of the randomized clinical trials re- ically hypoxic [partial oxygen pressure (pO2) < ferred to above included the tacit assumption that 10 mmHg]. Following this prediction, many clinical all tumors had radiobiologically significant hyp- studies have reported that human tumors are hyp- oxia. It is highly likely that a subset of tumors oxic and that hypoxia reduces the likelihood for local was not hypoxic and, therefore, would not benefit tumor control after radiotherapy or chemoradiother- from hypoxia modification. The presence of non- apy (4). The first tests of associations between hyp- hypoxic tumors in the overall population would oxia and radiotherapy or radiochemotherapy out- reduce the power to detect differences between come used invasive polarographic electrodes. As an control and hypoxia modification groups. If hyp- example, in a metaanalysis of head and neck cancer pa- oxia measurement were used as a selection tool, it tients treated with radiotherapy or chemoradiotherapy, is highly likely that these trials would have shown a aDepartment of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710 Author contributions: M.W.D. wrote the paper. The author declares no conflict of interest. Published under the PNAS license. See companion article on page 10756. 1Email: [email protected]. Published online October 9, 2018. 10548–10550 | PNAS | October 16, 2018 | vol. 115 | no. 42 www.pnas.org/cgi/doi/10.1073/pnas.1814212115 Downloaded by guest on September 24, 2021 Fig. 1. Sensitivity study examining three methods to reduce tumor hypoxia. This sensitivity study used oxygen transport modeling with Green’s functions to compare three methods for eliminating hypoxia in tumors. The Green’s function method allows for input of actual experimental data: (i) vascular geometry; (ii) flow direction, flow velocity, and vascular pO2 of the vascular segments within the network; and (iii) oxygen consumption rate. The Green’s function computes the pO2 at each location within the field, assuming O2 diffusion from the microvessels. This simulation used confocal imaging to obtain vascular geometry from a tumor growing in skin fold window chamber (Left). Baseline oxygen 3 −1 −1 consumption rate of 1.5 cm O2·100 g ·min was measured previously. Center depicts the network from the bottom, where the feeding vessels are located (vascular pO2 = 50 mmHg). The baseline condition for the central plane of the 500-μm × 500-μm × 200-μm tissue cube is 125 μm from the feeding vessels. Note that the pO2 of this plane is not influenced by the feeding vessels because distance between the plane and these vessels is near the diffusion distance of oxygen. The pO2 distribution depicts radial gradients of oxygen concentration from the vasculature, with significant variation, from near zero, to a maximum close to that of the feeding vessels (40 mmHg). The sensitivity study addressed the question of what relative change in vascular pO2 (Prel), flow rate (Qrel), or oxygen consumption rate (Mrel) would be required to reduce the hypoxic fraction to zero. Right shows the predictions. At baseline, the hypoxic fraction (percent volume <1 mmHg) is ∼12%. Increasing vascular pO2 required a 10× increase in O2 content of breathing gas, above air breathing conditions to eliminate hypoxia. This translates to hyperbaric treatment at 2 atm O2. A threefold increase in flow velocity is of intermediate efficiency in eliminating hypoxia. However, the most efficient means to eliminate hypoxia is by reducing oxygen consumption rate by 30%. Mrel,Prel,andQrel all compared to the baseline condition, as depicted in Center. Left and Right reprinted with permission from ref. 14, Springer Nature: Advances in Experimental Medicine and Biology, copyright (1998). Center has not been published previously. greater benefit (8). Methods to measure hypoxia were not increased tumor pO2, with the majority of measurements ex- available at the time of many early trials, but this is not the ceeding the 10-mmHg threshold for radiobiologic hypoxia (15). case now. For example, PET and single-photon emission com- iii) Some hypoxia modification strategies were toxic. Key exam- puted tomography (SPECT) tracers (9), certain MRI and CT ples include the 2-nitroimidazole hypoxia mimics. These endpoints (9), and optical spectroscopy (10, 11) effectively drugs mimicked the activity of oxygen by interacting with predict or directly assess the extent or severity of hypoxia, DNA adducts in irradiated cells (12). Despite very promising respectively. Future trials should include measurement of ex- preclinical results, the lead drugs caused peripheral neurotox- tent of hypoxia as an entry criterion for trial accrual. icity in human trials. This toxicity contributed to failure in many ii) Attempts to reduce hypoxia by increasing delivery are not randomized trials, because of drug dose-schedule limitations efficient. The vast majority of approaches to reduce tumor (16). One drug of this class, nimorazole, demonstrated less hypoxia focused on means to increase delivery (12). This is toxicity and is a standard of care in Denmark in combination the least efficient option, however. We compared the efficien- with radiotherapy (12). Designed to selectively kill hypoxic ’ cies of methods to reduce hypoxia, using Green s function tumor cells, derivatives of the classic 2-nitroimidazole com- calculations that were based on detailed microcirculatory pounds kill hypoxic cells after prolonged exposure (16). The measurements (13, 14). Reduction in oxygen consumption classic example is tirapazamine. In clinical trials, this drug rate was predicted to be 30-fold more efficient in reducing caused muscle toxicity, which also limited the drug dose hypoxia than increasing oxygen delivery by methods such as schedule (17). Although early trials were promising, tirapaz- breathing hyperbaric oxygen or carbogen (Fig. 1). Further, we amine ultimately failed in phase III trials (18, 19). Newer classes predicted that only a 30% reduction in oxygen consumption of the hypoxic cytotoxins, including prodrugs converted to rate would be sufficient to eliminate hypoxia. Here, Benej toxic intermediaries in hypoxic conditions, may yield a thera- et al. (1) demonstrate that a 30 to 50% reduction in oxygen peutic advantage because they
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