Therapeutic Modification of Hypoxia

M.R Horsman,B.S Sørensen,M Busk,D.W Siemann

doi:10.1016/j.clon.2021.08.014

Abstract

Regions of reduced oxygenation (hypoxia) are a characteristic feature of virtually all animal and human solid tumours. Numerous preclinical studies, both in vitro and in vivo, have shown that decreasing oxygen concentration induces resistance to radiation. Importantly, hypoxia in human tumours is a negative indicator of radiotherapy outcome. Hypoxia also contributes to resistance to other cancer therapeutics, including immunotherapy, and increases malignant progression as well as cancer cell dissemination. Consequently, substantial effort has been made to detect hypoxia in human tumours and identify realistic approaches to overcome hypoxia and improve cancer therapy outcomes. Hypoxia-targeting strategies include improving oxygen availability, sensitising hypoxic cells to radiation, preferentially killing these cells, locating the hypoxic regions in tumours and increasing the radiation dose to those areas, or applying high energy transfer radiation, which is less affected by hypoxia. Despite numerous clinical studies with each of these hypoxia-modifying approaches, many of which improved both local tumour control and overall survival, hypoxic modification has not been established in routine clinical practice. Here we review the background and significance of hypoxia, how it can be imaged clinically and focus on the various hypoxia-modifying techniques that have undergone, or are currently in, clinical evaluation.

Highlights

Introduction and Historical PerspectivesThe history of tumour hypoxia began more than 100 years ago, when two studies showed that if the blood flow to a tissue was changed Author for correspondence: M.R
Later investigations using broad bean (Vicia faba) roots [3e5], Tradescantia microspores [6,7], Escherichia coli [8], Drosophila melanogaster [9] and even cancer cells [10] clearly showed that oxygen was important for radiation sensitivity
Hypoxia is a characteristic feature of virtually all solid tumours

Summary

Introduction and Historical Perspectives

The history of tumour hypoxia (regions of low oxygenation) began more than 100 years ago, when two studies showed that if the blood flow to a tissue was changed . Preclinical in vitro studies showed preferential radiosensitisation of hypoxic cells by highly electron-affinic nitroaromatic compounds [145,146] These agents had no radiosensitising effect under normoxic conditions, but under hypoxia underwent reduction to a reactive product that, like oxygen, could react with the radicals formed in the DNA by radiation. Results from the early in vitro preclinical studies with electron-affinic radiosensitisers had shown that these drugs enhanced the radiation response of hypoxic cells, but not aerobic cells [146] This preferential effect was observed in terms of drug toxicity [156,157] and, like the radiosensitising effect, was the consequence of a reduction of the molecule’s nitro group from an inactive form to an active moiety under hypoxia. Increasing the LET will reduce the impact of hypoxia, even using radiation with the highest clinically tolerable LET, hypoxia will only be eliminated if some form of modifier is included in the treatment regimen

Conclusions and Future Perspectives

Findings

Conflicts of interest