Exploring hypoxic biology to improve radiotherapy outcomes

Abstract

Ionising radiotherapy is a well-established, effective cancer treatment modality, whose efficacy has improved with the application of newer technological modalities. However, patient outcomes are governed and potentially limited by aspects of tumour biology that are associated with radioresistance. Patients also still endure treatment-associated toxicities owed to the action of ionising radiation in normoxic tissue adjacent to the tumour mass. Tumour hypoxia is recognised as a key component of the tumour microenvironment and is well established as leading to therapy resistance and poor prognosis. In this review, we outline the current understanding of hypoxia-mediated radiotherapy resistance, before exploring targeting tumour hypoxia for radiotherapy sensitisation to improve treatment outcomes and increase the therapeutic window. This includes increasing oxygen availability in solid tumours, the use of hypoxia-activated prodrugs, targeting of hypoxia-regulated or associated signalling pathways, as well as the use of high-LET radiotherapy modalities. Ultimately, targeting hypoxic radiobiology combined with precise radiotherapy delivery modalities and modelling should be associated with improvement to patient outcomes.

Positron emission tomography imaging sheds new light on hypoxia and antitumor therapies

“…During the process, high‐energy photons from X‐rays or gamma rays produce DNA free radicals (DNA%), which are rapidly oxidized by oxygen, leading to the break of DNA double strands, formation of oxidized bases, and eventually cell death 40 . Under normoxic conditions, due to the presence of sufficient oxygen, reactive oxygen species (ROS) and hydrogen peroxide are produced efficiently 41 . Besides, free radicals generated from critical targets (R·) can also react with oxygen to produce first peroxyl radicals (ROO·) and ultimately ROOH, a more stable and detrimental free radical 42 …”

“…40 Under normoxic conditions, due to the presence of sufficient oxygen, reactive oxygen species (ROS) and hydrogen peroxide are produced efficiently. 41 Besides, free radicals generated from critical targets (R•) can also react with oxygen to produce first peroxyl radicals (ROO•) and ultimately ROOH, a more stable and detrimental free radical. 42 However, under hypoxic conditions, these reactions are limited due to the lack of oxygen and instability of the free radicals, leading to more repairable damages for tumor cells.…”

Application of Gold Nanoparticles as Radiosensitizer for Metastatic Prostate Cancer Cell Lines

“…One of the main challenges regarding the efficacy of RT is the presence of hypoxic tumor cells. These cells can contribute to the enhancement of radiation resistance due to the reduced production of reactive oxygen species (ROS) and, consequently, a decrease in oxidative stress and apoptosis [ 4 ]. Another clinical problem in PCa treatment is recurrence.…”

Radiation Therapy for Gestational Trophoblastic Neoplasia: Forward-Looking Lessons Learnt

“…The malignant opposing parts of the extra-villous interstitial-implantation-site-like trophoblasts are the placental site trophoblastic tumour and epithelioid trophoblastic tumour that develop less necrotic, haemorrhagic, uterine lesions with lower vascular invasion. If, on the one hand, the haemorrhagic tendency justifies the haemostatic role of RT, on the other hand, the high rate of necrosis is a radioresistance hallmark that requires great attention in terms of fractionation schedules and radiation type [15][16][17][18]. RT has been used in the past mainly in the treatment of brain and liver metastases of GTNs.…”