Impact du fractionnement du traitement sur les propriétés radiosensibilisantes du bortézomib sur deux modèles de gliome malin humain xénogreffés

Abstract : Malignant gliomas are the most common neoplasm of the central nervous system and patients prognosis remains dismal, despite aggressive surgery, radio- and chemotherapy. Radiotherapy is a major treatment modality in this tumoral type but its usefulness is limited by normal brain tissue toxicity. The concomitant administration of a radiosensitizing agent is an innovative strategy to improve ionizing radiations efficacy. Bortezomib (Velcade®) belongs to a new class of anticancer agents, i.e. the proteasome inhibitors, and this molecule has been approved for the treatment of multiple myeloma. Our objectives are to study the radiosensitizing properties of bortezomib on two human malignant glioma models xenografted onto nude mice. Our work was designed to evaluate the impact of treatment fractionation on the antitumor activity of the concomitant association of bortezomib and radiotherapy. Our results show that bortezomib is a potent radiosensitizer on our two malignant glioma models but these properties are lost when treatments are fractionated according to a typical clinical schedule. In conditions of fractionated treatment, we demonstrate that bortezomib reduces the radio-induced apoptosis. This may be linked to the loss of the inhibitory properties of bortezomib secondary to consecutive infusions. We also evaluate the importance of the transcription factor NF-kB in the radioresponse of the malignant glioma xenografts used. Finally, our work emphasizes on the importance of performing preclinical studies using doses and therapeutic schedule mimicking the clinical settings to provide more predictive results of treatment response in Humans.
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Marianne Labussière. Impact du fractionnement du traitement sur les propriétés radiosensibilisantes du bortézomib sur deux modèles de gliome malin humain xénogreffés. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2008. Français. ⟨NNT : 2008NAN10132⟩. ⟨tel-01777269⟩

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