Erythropoietin-induced reduction of hypoxia before and during fractionated irradiation contributes to improvement of radioresponse in human glioma xenografts

Pinel, Sophie; Barberi‐Heyob, Muriel; Cohen–Jonathan, Elizabeth; Merlin, Jean‐Louis; Delmas, Caroline; Plénat, François; Chastagner, Pascal

doi:10.1016/j.ijrobp.2003.12.022

Cited by 51 publications

(44 citation statements)

References 39 publications

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“…Administration of rhEPO resulted in significantly better oxygenation in both tumour regions compared with control animals. This effect is attributable to an increased blood oxygen carrying capacity and has been observed in other preclinical models (Pinel et al, 2004).…”

Section: Discussionsupporting

confidence: 53%

“…Preclinical studies investigating the effect of exogenous rhEPO on tumour growth and angiogenesis are at present inconclusive (Hardee et al, 2005). Similarly, whereas some preclinical data suggest that rhEPO increases response to RT, chemotherapy or photodynamic therapy, other studies did not identify any effects of rhEPO (Stuben et al, 2003;Pinel et al, 2004;Kirkpatrick et al, 2006). In the clinical setting, the effects of rhEPO on locoregional control and survival of cancer patients treated with RT or chemotherapy are a matter of ongoing controversy.…”

Section: Discussionmentioning

confidence: 99%

“…Experimentally, exogenous rhEPO has been shown to improve or restore radioresponsiveness in both anaemic and nonanaemic animals (Thews et al, 1998;Stuben et al, 2003;Pinel et al, 2004). Interestingly, darbepoetin alfa, an EPO analogue with a longer half-life, did not enhance radioresponsiveness in a rat mammary adenocarcinoma model (Kirkpatrick et al, 2006).…”

mentioning

confidence: 99%

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Recombinant human erythropoietin α modulates the effects of radiotherapy on colorectal cancer microvessels

et al. 2007

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Recent data suggest that recombinant human erythropoietin (rhEPO) modulates tumour growth and therapy response. The purpose of the present study was to examine the modulation of radiotherapy (RT) effects on tumour microvessels by rhEPO in a rat colorectal cancer model. Before and after 5 Â 5 Gy of RT, dynamic contrast-enhanced -magnetic resonance imaging was performed and endothelial permeability surface product (PS), plasma flow (F), and blood volume (V) were modelled. Imaging was combined with pO 2 measurements, analysis of microvessel density, microvessel diameter, microvessel fractal dimension, and expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 a (HIF-1a), Bax, and Bcl-2. We found that RT significantly reduced PS and V in control rats, but not in rhEPO-treated rats, whereas F was unaffected by RT. Oxygenation was significantly better in rhEPOtreated animals, and RT induced a heterogeneous reoxygenation in both groups. Microvessel diameter was significantly larger in rhEPO animals, whereas VEGF expression was significantly lower in the rhEPO group. No differences were observed in HIF-1a, Bax, or Bcl-2 expression. We conclude that rhEPO results in spatially heterogeneous modulation of RT effects on tumour microvessels. Direct effects of rhEPO on neoplastic endothelium are likely to explain these findings in addition to indirect effects induced by increased oxygenation. British Journal of Cancer (2007) Anaemia commonly occurs in colorectal cancer patients especially if they are treated with neoadjuvant radiotherapy (RT) or chemotherapy. Anaemia not only adversely affects the clinical condition of these patients, but also contributes to the development of tumour hypoxia, recognised as a major negative determinant of sensitivity to RT, chemoradiotherapy, and certain chemotherapeutic agents (Harrison and Blackwell, 2004;van Halteren et al, 2004).Recent clinical studies have shown that administration of recombinant human erythropoietin (rhEPO, epoetin alfa) increases haemoglobin levels and improves quality of life in patients with cancer-related anaemia (Littlewood et al, 2001). Over the last decade, it has become clear that the action or rhEPO extends into a wide range of cellular mechanisms involved in stem cell development, maintenance of cellular integrity, and physiological angiogenesis (Maiese et al, 2005). The demonstration of the erythropoietin (EPO) receptor in various neoplastic tissues and the observation in a recent clinical trial that mortality was higher in nonanaemic rhEPO-treated breast cancer patients highlighted the possible effects of rhEPO on tumour growth and angiogenesis (Leyland-Jones, 2003). Preclinical studies investigating the role of EPO and EPO -EPO receptor signalling on tumour growth and angiogenesis have yielded contradictory results. Yasuda et al (2003) noted the inhibition of angiogenesis and tumour cell survival in stomach and melanoma xenografts following blockade of EPO signalling. The results of Hardee et al (2005), however, suggested that a...

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Recombinant human erythropoietin α modulates the effects of radiotherapy on colorectal cancer microvessels

et al. 2007

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“…an increased hemoglobin level increases intratumoral oxygenation (13), which may lead to improved response to radiation and chemotherapy (14,15). therefore, EpO has been used in various studies to increase tumor oxygenation in order to augment the effect of antineoplastic therapy (16)(17)(18). A specific indication during brain tumor treatment may protect against the cognitive impairment caused by radiochemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…in various systemic tumors, EpO was applied to sensitize tumors for radiation or chemotherapy. While certain studies observed beneficial effects (16)(17)(18), a lower survival rate was found in head-and-neck and breast cancer (22,23). apart from unclear effects on the tumor growth itself, systemic side effects including deep venous thrombosis or arterial hypertension may have worsened the patient outcome (24).…”

Section: Discussionmentioning

confidence: 99%

High expression levels of erythropoietin and its receptor are not correlated with shorter survival in human glioblastoma

Brunotte¹,

Bock

Brück

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Erythropoietin (EpO) is used to treat anemia in neoplastic disease. EpO also exerts neuroprotective effects on neuronal cells, making a prophylactic use against the neurocognitive effects of radiochemotherapy probable. however, EpO/ EpO-receptor (EpOr) signalling has been also detected in glioblastoma cells. data collected in vitro and in vivo show conflicting results on the effect of EPO on malignant gliomas. the association between EpO and EpOr expression and the prognosis of human glioblastomas was analyzed. probes of human glioblastomas with complete documentation of clinical course and treatment were assessed by immunohistochemistry for the expression of EpO and EpOr (n=80). using univariate and multivariate survival analysis, the association with age, gender, radiation, chemotherapy and extent of resection was determined. high levels of EpOr were correlated with a median survival advantage of 7 months (p<0.01). By univariate, but not multivariate, analysis, high levels of EpO and EpOr were associated with a significant prolongation of 7 months median survival when compared to low levels of both molecules. in patients treated with radiochemotherapy adjuvant to surgery, the median survival was 6.5 months longer in patients with high levels of EpOr (p<0.04). according to previous studies, longer patient survival is associated with EpOr expression. therefore, EpO appears to be safe for the treatment of anemia in glioblastoma patients. Ηowever, a prophylactic use, i.e., for neuroprotection, is not recommended in light of the functional studies described in the literature.

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Association Between Pharmaceutical Support and Basic Science Research on Erythropoiesis-Stimulating Agents

et al. 2010

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Background No prior study has evaluated financial relationships of investigators with pharmaceutical manufacturers for basic science. An example of the importance and impact of such relationships is in the evaluation of erythropoietin receptors’(EpoRs) effects on cancer cell lines, since studies have reported increased mortality when cancer patients receive erythropoiesis stimulating agents (ESAs). Purpose To assess the disclosed association that exist between pharmaceutical industry support and EpoRs effects on solid cancer cell lines. Data Sources MEDLINE and EMBASE (1988- July 2008) and two EpoR conferences sponsored by the National Institutes of Health. Study Selection All publications investigating EpoRs that met inclusion criteria were identified and included. Data Extraction Data were extracted on detection of EpoRs, presence of erythropoietin-induced signaling events, presence of erythropoietin-induced changes in cellular function, nature of qualitative conclusions, and sources of funding for all 74 studies. Data Synthesis In comparison to studies of academic investigators with no disclosed funding support from ESA manufacturers (n=64), the studies from academic investigators with funding support from ESA manufacturers (n= 7) and the laboratories directed by investigators employed by ESA manufacturers (n=3) were both less likely to identify: EpoR presence on solid tumor cells; erythropoietin-induced signaling events; erythropoietin-induced changes in cellular function; and less likely to conclude that their research had identified potentially harmful effects of erythropoietin on cancer cells. Additionally, presentations from industry-based investigator teams at NIH conferences were less likely to report EpoRs on cancer cell lines, downstream effects of erythropoietin, and cell proliferation and migration effects following EpoR administration. Conclusion Financial conflicts of interest impact the outcomes and presentation of basic science research data as well as publications.

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Erythropoietin-induced reduction of hypoxia before and during fractionated irradiation contributes to improvement of radioresponse in human glioma xenografts

Cited by 51 publications

References 39 publications

Recombinant human erythropoietin α modulates the effects of radiotherapy on colorectal cancer microvessels

Recombinant human erythropoietin α modulates the effects of radiotherapy on colorectal cancer microvessels

High expression levels of erythropoietin and its receptor are not correlated with shorter survival in human glioblastoma

Association Between Pharmaceutical Support and Basic Science Research on Erythropoiesis-Stimulating Agents

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