Radiotherapy in Conjunction with 7-Hydroxystaurosporine: A Multimodal Approach with Tumor pO<sub>2</sub>as a Potential Marker of Therapeutic Response

Khan, Nadeem; Mupparaju, Sriram P.; Hou, Huagang; Lariviere, Jean P.; Demidenko, Eugene; Swartz, Harold M.; Eastman, Alan

doi:10.1667/rr1781.1

Cited by 6 publications

(5 citation statements)

References 30 publications

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“…This method has proven to be useful to identify possible areas of resistance during modulations of tumor hypoxia using drugs and anti-angiogenic treatments (35–38). EPR oximetric imaging, however provides quantitative information on oxygenation and hypoxia from the whole imaged volume, and is therefore a more thorough tool to identify the hypoxic fractions within the tumors in order to improve the therapy outcome (23,39).…”

Section: Discussionmentioning

confidence: 99%

EPR Oxygen Images Predict Tumor Control by a 50% Tumor Control Radiation Dose

et al. 2013

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Clinical trials to ameliorate hypoxia as a strategy to relieve the radiation resistance it causes have prompted a need to assay the precise extent and location of hypoxia in tumors. Electron Paramagnetic Resonance oxygen imaging (EPR O2 imaging) provides a non-invasive means to address this need. To obtain a preclinical proof of principle that EPR O2 images could predict radiation control, we treated mouse tumors at or near doses required to achieve 50 percent control (TCD50). Mice with FSa fibrosarcoma or MCa4 carcinoma were subjected to EPR O2 imaging and immediately radiated to a TCD50 or TCD50 ±10 Gy.. Statistical analysis was permitted by collection of ~ 1300 tumor pO2 image voxels, including the fraction of tumor voxels with pO2 less than 10 mm Hg (HF10). Tumors were followed for 90 days (FSa) or 120 days (MCa4) to determine local control or failure. HF10 obtained from EPR images showed statistically significant differences between tumors that were controlled by the TCD50 and those that were not controlled for both FSa and MCa4. Kaplan-Meier analysis of both types of tumors showed ~90% of mildly hypoxic tumors were controlled (HF10<10%), and only 37% (FSA) and 23% (MCa4) tumors controlled if hypoxic. EPR pO2 image voxel distributions in these ~0.5 ml tumors provide a prediction of radiation curability independent of radiation dose. These data confirm the significance of EPR pO2 hypoxic fractions. The ~90% control of low HF10 tumors argue that ½ ml subvolumes of tumors may be more sensitive to radiation and may need less radiation for high tumor control rates.

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Section: Discussionmentioning

confidence: 99%

EPR Oxygen Images Predict Tumor Control by a 50% Tumor Control Radiation Dose

et al. 2013

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“…Given the significant role of tumor hypoxia in therapeutic resistance and malignant progression, it is vital to develop strategies that can alleviate hypoxia as well as inhibit glioma growth. We have previously investigated the effect of an allosteric effector of hemoglobin (Efaproxiral), carbogen inhalation and radiotherapy on tumor pO 2 in orthotopic 9L, C6, CNS-1 and F98 glioma 11, 12, 33, 34 . Our goal is to characterize temporal changes in glioma pO 2 , improve oxygen level and treatment outcome.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously investigated the effect of an allosteric effector of hemoglobin (Efaproxiral), carbogen inhalation and radiotherapy on tumor pO 2 in orthotopic 9L, C6, CNS-1 and F98 glioma. [11][12][13][14]33,34 Our goal is to characterize temporal changes in glioma pO 2 , improve oxygen level and treatment outcome. In this study, we have implemented a novel implantable resonator for monitoring cerebral pO 2 including orthotopic glioma in mice with EPR oximetry.…”

Section: Discussionmentioning

confidence: 99%

Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator‐based oximetry

Hou

Nemani

et al. 2014

Intl Journal of Cancer

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Hypoxia is a critical hallmark of glioma, and significantly compromises treatment efficacy. Unfortunately, techniques for monitoring glioma pO2 to facilitate translational research are lacking. Furthermore, poor prognoses of patients with malignant glioma, in particular glioblastoma multiforme, warrant effective strategies that can inhibit hypoxia and improve treatment outcome. EPR oximetry using implantable resonators was implemented for monitoring pO2 in normal cerebral tissue and U251 glioma in mice. Breathing carbogen (95% O2 + 5% CO2) was tested for hyperoxia in the normal brain and glioma xenografts. A new strategy to inhibit glioma growth by rationally combining gemcitabine and MK-8776, a cell cycle checkpoint inhibitor, was also investigated. The mean pO2 of left and right hemisphere were approximately 56 – 69 mmHg in the normal cerebral tissue of mice. The mean baseline pO2 of U251 glioma on the first and fifth day of measurement was 21.9 ± 3.7 and 14.1 ± 2.4 mmHg, respectively. The mean brain pO2 including glioma increased by at least 100% on carbogen inhalation, although the response varied between the animals over days. Treatment with gemcitabine + MK-8776 significantly increased pO2 and inhibited glioma growth assessed by MRI. In conclusion, EPR oximetry with implantable resonators can be used to monitor the efficacy of carbogen inhalation and chemotherapy on orthotopic glioma in mice. The increase in glioma pO2 of mice breathing carbogen can be used to improve treatment outcome. The treatment with gemcitabine + MK-8776 is a promising strategy that warrants further investigation.

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“…Since then, EPR oximetry has been engaged as a useful tool to measure the physiological concentrations of pO 2 in various tissues. EPR oximetry studies over recent years have included the development and testing of new paramagnetic spin probes 17, 19, pO 2 measurements in tumors 12, 14, 16–18, comparison with other methods 20 and monitoring of the dynamic changes in oxygen in tumors by modifying inhaled gases 12, 15–17, 21 or by pharmacological interventions 21. Thus, the majority of efforts have concentrated on the measurement of oxygen tension in tumors and the monitoring of pO 2 changes during the course of therapy 12, 14, 16, 17.…”

Section: Methods Of Noninvasive Imaging Of Hypoxiamentioning

confidence: 99%

Hypoxic stress and cancer: imaging the axis of evil in tumor metastasis

2011

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Tumors emerge as a result of sequential acquisition of genetic, epigenetic, and somatic alterations promoting cell proliferation and survival. The maintenance and expansion of tumor cells relies on their ability to adapt to changes in their microenvironment, along with acquisition of the ability to remodel their surroundings. Tumor cells interact with two types of interconnected microenvironments, the metabolic cell autonomous microenvironment and the non-autonomous cellular-molecular microenvironment comprising interactions between tumor cells and the surrounding stroma. Hypoxia is a central player in cancer progression, affecting not only tumor cell autonomous functions such as cell division and invasion, resistance to therapy and genetic instability, but also non-autonomous processes such as angiogenesis, lymphangiogenesis and inflammation, all contributing to metastasis. Closely related microenvironmental stressors, affecting cancer progression include in addition to hypoxia, also elevated interstitial pressure and oxidative stress. Non invasive imaging offers multiple means for monitoring the tumor microenvironment and its consequences, and can thus assist in understanding the biological basis of hypoxia and microenvironmental stress in cancer progression, and in development of strategies for monitoring therapies targeted at stress induced tumor progression.

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Radiotherapy in Conjunction with 7-Hydroxystaurosporine: A Multimodal Approach with Tumor pO₂as a Potential Marker of Therapeutic Response

Cited by 6 publications

References 30 publications

EPR Oxygen Images Predict Tumor Control by a 50% Tumor Control Radiation Dose

EPR Oxygen Images Predict Tumor Control by a 50% Tumor Control Radiation Dose

Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator‐based oximetry

Hypoxic stress and cancer: imaging the axis of evil in tumor metastasis

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Radiotherapy in Conjunction with 7-Hydroxystaurosporine: A Multimodal Approach with Tumor pO2as a Potential Marker of Therapeutic Response

Cited by 6 publications

References 30 publications

EPR Oxygen Images Predict Tumor Control by a 50% Tumor Control Radiation Dose

EPR Oxygen Images Predict Tumor Control by a 50% Tumor Control Radiation Dose

Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator‐based oximetry

Hypoxic stress and cancer: imaging the axis of evil in tumor metastasis

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Radiotherapy in Conjunction with 7-Hydroxystaurosporine: A Multimodal Approach with Tumor pO₂as a Potential Marker of Therapeutic Response