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Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia.

ABSTRACT: Glioblastoma multiforme (GBM) is the most common and lethal form of brain cancer and these tumors are highly resistant to chemo- and radiotherapy. Radioresistance is thought to result from a paucity of molecular oxygen in hypoxic tumor regions, resulting in reduced DNA damage and enhanced cellular defense mechanisms. Efforts to counteract tumor hypoxia during radiotherapy are limited by an attendant increase in the sensitivity of healthy brain tissue to radiation. However, the presence of heightened levels of molecular oxygen during radiotherapy, while conventionally deemed critical for adjuvant oxygen therapy to sensitize hypoxic tumor tissue, might not actually be necessary. We evaluated the concept that pre-treating tumor tissue by transiently elevating tissue oxygenation prior to radiation exposure could increase the efficacy of radiotherapy, even when radiotherapy is administered after the return of tumor tissue oxygen to hypoxic baseline levels. Using nude mice bearing intracranial U87-luciferase xenografts, and in vitro models of tumor hypoxia, the efficacy of oxygen pretreatment for producing radiosensitization was tested. Oxygen-induced radiosensitization of tumor tissue was observed in GBM xenografts, as seen by suppression of tumor growth and increased survival. Additionally, rodent and human glioma cells, and human glioma stem cells, exhibited prolonged enhanced vulnerability to radiation after oxygen pretreatment in vitro, even when radiation was delivered under hypoxic conditions. Over-expression of HIF-1? reduced this radiosensitization, indicating that this effect is mediated, in part, via a change in HIF-1-dependent mechanisms. Importantly, an identical duration of transient hyperoxic exposure does not sensitize normal human astrocytes to radiation in vitro. Taken together, these results indicate that briefly pre-treating tumors with elevated levels of oxygen prior to radiotherapy may represent a means for selectively targeting radiation-resistant hypoxic cancer cells, and could serve as a safe and effective adjuvant to radiation therapy for patients with GBM.

SUBMITTER: Clarke RH

PROVIDER: S-EPMC4211739 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia.

Clarke Ryon H RH Moosa Shayan S Anzivino Matthew M Wang Yi Y Floyd Desiree Hunt DH Purow Benjamin W BW Lee Kevin S KS

PloS one 20141028 10

Glioblastoma multiforme (GBM) is the most common and lethal form of brain cancer and these tumors are highly resistant to chemo- and radiotherapy. Radioresistance is thought to result from a paucity of molecular oxygen in hypoxic tumor regions, resulting in reduced DNA damage and enhanced cellular defense mechanisms. Efforts to counteract tumor hypoxia during radiotherapy are limited by an attendant increase in the sensitivity of healthy brain tissue to radiation. However, the presence of height ...[more]

PMID: 25350400

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Project description:Treatment of malignant glioma is a challenge facing cancer therapy. In addition to surgery, and chemotherapy, radiotherapy (RT) is one of the most effective modalities of glioma treatment. However, there are two crucial challenges for RT facing malignant glioma therapy: first, gliomas are known to be resistant to radiation due to their intratumoral hypoxia; second, radiosensitizers may exhibit a lack of target specificity, which may cause a lower concentration of radiosensitizers in tumors and toxic side effects in normal tissues. Thus, novel angiopep-2-lipid-poly-(metronidazoles)n (ALP-(MIs)n) hypoxic radiosensitizer-polyprodrug nanoparticles (NPs) were designed to enhance the radiosensitizing effect on gliomas. Methods: In this study, different degrees and biodegradabilites of hypoxic radiosensitizer MIs-based polyprodrug (P-(MIs)n) were synthesized as a hydrophobic core. P-(MIs)n were mixed with DSPE-PEG2000, angiopep-2-DSPE-PEG2000 and lecithin to self-assemble ALP-(MIs)n through a single-step nanoprecipitation method. The ALP-(MIs)n encapsulate doxorubicin (DOX) (ALP-(MIs)n/DOX) and provoke the release of DOX under hypoxic conditions for glioma chemo- and radiotherapy. In vivo glioma targeting was tested in an orthotopic glioma using live animal fluorescence/bioluminescence imaging. The effect on sensitization to RT of ALP-(MIs)n and the combination of chemotherapy and RT of ALP-(MIs)n/DOX for glioma treatment were also investigated both in vitro and in vivo. Results: ALP-(MIs)n/DOX effectively accumulated in gliomas and could reach the hypoxic glioma site after systemic in vivo administration. These ALP-(MIs)n showed a significant radiosensitizing effect on gliomas and realized combination chemotherapy and RT for glioma treatment both in vitro and in vivo. Conclusions: In summary, we constructed a lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for enhancing the RT sensitivity of gliomas and achieving the combination of radiation and chemotherapy for gliomas.

Dataset Information

Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia.

Publications

Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia.

Similar Datasets

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