78 AUTOPHAGY INDUCTION DURING IRRADITION TREATMENT IN HUMAN ORAL CANCER

Abstract

monitoring of tumor hypoxia and demonstrated a transient increase in tumor hypoxia in response to treatment with patupilone alone. To investigate whether the supra-additive tumor growth delay effect of the combined treatment modality (patupilone/IR) is influenced by the level of patupilone-increased tumor hypoxia, tumors were irradiated at the time point of the lowest and the highest level of patupilone-increased tumor hypoxia. Interestingly the hypoxia-inducing effect of patupilone dominated over the effect of the combined treatment modality on the level of tumor hypoxia, but had no effect on efficacy-related endpoints. In parallel the metabolic status of A549 tumors was determined ex vivo by the immersion of dried/heat-inactivated tumor sections in an ATP, lactate or glucose-depending luciferase-containing buffer system. Integrated light output was detected in a highly sensitive bioluminescent detection system (IVIS). Treatment of A549 wild type tumors with patupilone, IR and in combination significantly reduced lactate levels and drastically increased glucose levels in comparison to untreated tumors. Interestingly, these changes were only minimal in tumors derived from patupilone-resistant cells (A549EpoB40). ATP levels of all tumors tested did not change under any treatment. When compared with other histological endpoints, basal and treatment-dependent changes of lactate levels in the different tumors did not correlate with basal and treatment-induced changes of tumor hypoxia or microvessel density, but mainly correlated with the proliferative activity and the tumor growth response to treatment. This study shows that the tumor milieu is responsive to different treatment-modalities and that detailed insights into the dynamics of hypoxia and metabolism will contribute to the improvement and adaptation of existing radiochemotherapies.