Tumor hypoxia and reoxygenation: the yin and yang for radiotherapy

Abstract

Tumor hypoxia, a common feature occurring in nearly all human solid tumors is a major contributing factor for failures of anticancer therapies. Because ionizing radiation depends heavily on the presence of molecular oxygen to produce cytotoxic effect, the negative impact of tumor hypoxia had long been recognized. In this review, we will highlight some of the past attempts to overcome tumor hypoxia including hypoxic radiosensitizers and hypoxia-selective cytotoxin. Although they were (still are) a very clever idea, they lacked clinical efficacy largely because of 'reoxygenation' phenomenon occurring in the conventional low dose hyperfractionation radiotherapy prevented proper activation of these compounds. Recent meta-analysis and imaging studies do however indicate that there may be a significant clinical benefit in lowering the locoregional failures by using these compounds. Latest technological advancement in radiotherapy has allowed to deliver high doses of radiation conformally to the tumor volume. Although this technology has brought superb clinical responses for many types of cancer, recent modeling studies have predicted that tumor hypoxia is even more serious because 'reoxygenation' is low thereby leaving a large portion of hypoxic tumor cells behind. Wouldn't it be then reasonable to combine hypoxic radiosensitizers and/or hypoxia-selective cytotoxin with the latest radiotherapy? We will provide some preclinical and clinical evidence to support this idea hoping to revamp an enthusiasm for hypoxic radiosensitizers or hypoxia-selective cytotoxins as an adjunct therapy for radiotherapy.

Keywords: Hyperfractionation; Hypofractionation; Hypoxia; Hypoxia-selective cytotoxin; Radiosensitizers; Reoxygenation.

Fig. 1.

A diagram demonstrating chronic hypoxia (left) and acute hypoxia (right).

Fig. 2.

Hypoxic radiosensitizers. (A) Hypoxic selective mechanism of action for nitroimidazole class (R-NO₂) of radiosensitizers. (B) Chemical structure of metronidazole and misonidazole.

Fig. 3.

Hypoxic selective mechanism of action for tirapazamine.

Fig. 4.

Locoregional failure by treatment arm and hypoxia. Tirapazamine offers a significant benefit lowering the locoregional failures in head and neck cancer patients with hypoxia (red box). TPZ/CIS, tirapazamine/cisplatin; RT, radiotherapy. Modified from Rischin et al. [36] with permission of the American Society of Clinical Oncology.

Fig. 5.

Tumor hypoxia is dynamically changing. (A) A positron emission tomography-computed tomography (PET-CT) image (left) and intensity-modulated radiotherapy (IMRT) treatment (right) for a patient whom do not demonstrate a significant change in the tumor hypoxia as examined by two consecutive ¹⁸F-misonidazole (¹⁸F-MISO) images (left). (B) A significant change in the location of tumor hypoxia is noted in this patient between 1st (red area) and 2nd (green area) images of F-MISO PET (left). Upon IMRT treatment (right), newly hypoxic areas (green) would receive the dose not enough to kill hypoxic cells while those tumor areas that are no longer hypoxic would experience overdose of irradiation. Adapted from Lin et al. [38] with permission of Elsevier.

Fig. 6.

Total surviving clones as a function of dose per fraction assuming daily fractionation and full reoxygenation between fractions. A: For tumors with 10% hypoxia (f_hyp = 0.1; red line) there is more than 2 logs (100-fold) of cell survival advantage (pointed with the orange arrow) as we reduce the number of fractionations (as we shift right to left). B: As hypoxic fraction increases from 10% (f_hyp = 0.1; red line) to 30% (f_hyp = 0.3; green line), there is additional 1 log (10-fold) of cell survival increase (pointed with the black arrow) at 5 fractionation treatment, at which the cell survival is already being much higher than that by hyperfractionation. Adapted from Carlson et al. [43] with permission of Elsevier.

Fig. 7.

Survival curves of Chinese hamster ovary (CHO) cells irradiated under oxic (O₂), hypoxic (N₂), or hypoxic conditions in the presence of 1.5 mM misonidazole (red line) by 270 kVp X-ray irradiation at (A) high or (B) low dose range. Note that sensitization enhancement ratio (yellow arrows) of misonidazole is larger at higher irradiation dose range (A). Adapted from Palcic et al. [51] with permission of publisher.

Fig. 8.

A diagram demonstrating development of hypoxic radiosensitizers and hypoxia-selective cytotoxins. Reoxygenation by the conventional low doses hyperfractionation radiotherapy had previously been interfered with proper activation of those compounds in tumors. Because interfractionation reoxygenation is now being predicted to be low with the latest high doses hypofractionation radiotherapy stereotactic body radiotherapy (SBRT), perhaps it is sufficiently reasonable to combine hypoxic radiosensitizers or hypoxia-selective cytotoxins with such radiotherapy techniques. PET, positron-emission tomography.