Abstract
Tumor hypoxia is one of the most important parameters that determines treatment sensitivity and is mainly due to insufficient tumor angiogenesis. However, the local oxygen concentration in a tumor can also be shifted in response to different treatment modalities such as cytotoxic agents or ionizing radiation. Thus, combined treatment modalities including microtubule stabilizing agents could create an additional challenge for an effective treatment response due to treatment-induced shifts in tumor oxygenation. Tumor hypoxia was probed over a prolonged observation period in response to treatment with different cytotoxic agents, using a non-invasive bioluminescent ODD-Luc reporter system, in which part of the oxygen-dependent degradation (ODD) domain of HIF-1α is fused to luciferase. As demonstrated in vitro, this system not only detects hypoxia at an ambient oxygen concentration of 1% O2, but also discriminates low oxygen concentrations in the range from 0.2 to 1% O2. Treatment of A549 lung adenocarcinoma-derived tumor xenografts with the microtubule stabilizing agent patupilone resulted in a prolonged increase in tumor hypoxia, which could be used as marker for its antitumoral treatment response, while irradiation did not induce detectable changes in tumor hypoxia. Furthermore, despite patupilone-induced hypoxia, the potency of ionizing radiation (IR) was not reduced as part of a concomitant or adjuvant combined treatment modality.
Highlights
Hypoxia is one of the most important parameters that cause enhanced tumor aggressiveness and treatment resistance, and hypoxia is considered to be an independent prognostic indicator of poor outcome for different tumor entities
This construct is constantly expressed in cells under control of a minimal, hypoxia-independent, SV40-promoter to be rapidly degraded under normoxic conditions, and slightly differs from previously used oxygen-dependent degradation (ODD)-based constructs [29,39]
The ODD-sequence derives from the originally-identified human oxygen-dependent degradation domain (ODD) of HIF-1a but includes only the sequence coding for aa530 to aa652
Summary
Hypoxia is one of the most important parameters that cause enhanced tumor aggressiveness and treatment resistance, and hypoxia is considered to be an independent prognostic indicator of poor outcome for different tumor entities. Alternating periods of hypoxia and normoxia in the tumor support the selection of tumor cells with elevated mutation frequency with a more stress resistant and aggressive phenotype. Independent of the cellular genotype, hypoxic cells are more treatment resistant than normoxic cells, in particular towards ionizing radiation (IR). The oxygenation fixation theory implies that radiationinduced free radical sites in the DNA are chemically derivatized (‘‘fixed’’) in the presence of oxygen so that they can not be repaired and accumulate, leading to an enhanced rate of cell death. Thereby, normoxic cells are two- to three-fold more radiation sensitive than cells under hypoxia [1,2]
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