Review: Implications of In Vitro Research on the Effect of Radiotherapy and Chemotherapy Under Hypoxic Conditions

Abstract

LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Argue why hypoxic regions in solid tumors often contain viable cells that are intrinsically more resistant to treatment with radiotherapy or chemotherapy.2. Describe how exposure of cells or cell lines to hypoxic conditions has major implications on multiple intracellular pathways.3. Evaluate the importance of investigating chemoradiotherapy combinations in vitro under both normoxic and hypoxic conditions.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTAs it is now well established that human solid tumors frequently contain a substantial fraction of cells that are hypoxic, more and more in vitro research is focusing on the impact of hypoxia on the outcome of radiotherapy and chemotherapy. Indeed, the efficacy of irradiation and many cytotoxic drugs relies on an adequate oxygen supply. Consequently, hypoxic regions in solid tumors often contain viable cells that are intrinsically more resistant to treatment with radiotherapy or chemotherapy. Moreover, efforts have been made to exploit hypoxia as a potential difference between malignant and normal tissues. Nowadays, a body of evidence indicates that oxygen deficiency clearly influences some major intracellular pathways such as those involved in cell proliferation, cell cycle progression, apoptosis, cell adhesion, and others. Obviously, when investigating the effects of radiotherapy or chemotherapy or both combined under hypoxic conditions, it is essential to consider the influences of hypoxia itself on the cell. In this review, we first focus on the effects of hypoxia per se on some critical biological pathways. Next, we sketch an overview of preclinical and clinical research on radiotherapy, chemotherapy, and chemoradiation under hypoxic conditions. The Oncologist 2007;12: 690 -712

Sleep-disordered Breathing and Cancer Mortality

“…However, our observations are consistent with our a priori hypothesis, grounded on evidence from recent in vitro and animal studies on the effects of hypoxia in cancer progression. Cancer cells subjected to either chronic (8)(9)(10) or intermittent hypoxia (11) show increased resistance to therapy (e.g., radiation) and malignant progression. Furthermore, recent experiments in a melanoma-injected mouse model demonstrate that intermittent hypoxia mimicking sleep apnea in humans increases tumor growth (12).…”

“…Chronic hypoxia, a common feature in solid tumor tissue, has been associated with therapeutic resistance, tumor progression, and metastatic potential (8)(9)(10). In vitro studies have further demonstrated that cultured lung cancer cells subject to intermittent hypoxia are more resistant to radiation and apoptosis and are more prone to metastasis (11).…”

CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth

“…45,46 Therefore, the use of CDK inhibitors to reduce HIF-1 activity may be a useful strategy in combination with therapies that are currently used in the clinic. Here, we show that inhibition of CDK1 and CDK4 dramatically reduces HIF-1 activity in both normoxic and hypoxic environments.…”

Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

“…Hypoxia and HIF-1 contribute to the poor response to anticancer therapy by several mechanisms (Cosse and Michiels, 2008;Tredan et al, 2007;Wouters et al, 2007). Indeed, HIF-1 activation allows expression of a battery of genes involved in survival and cell resistance to chemotherapy.…”