Role of the microenvironment for radiosensitization by patupilone

Abstract

Purpose: The combined treatment modality of ionizing radiation and the clinically relevant microtubule-stabilizing compound patupilone (epothilone B, EPO906) is a promising approach for anti-cancer therapy. Here we investigated the role of the tumor microenvironment for the supra-additive in vivo response in tumor xenografts derived from patupilone-sensitive and patupilone resistant non-small cell lung cancer cells.
Experimental Design: The treatment response to a combined regimen of patupilone and ionizing radiation was investigated in vitro and in tumor xenografts derived from wildtype A549 and A549.EpoB40 cells which are resistant to patupilone due to a β-tubulin mutation.
Results: In both A549 and A549.EpoB40 cells proliferative activity and clonogenicity were reduced in response to ionizing radiation, while patupilone, as expected, inhibited proliferation of the mutant cell line with reduced potency. Combined treatment with patupilone and ionizing radiation induced a cytotoxic effect in an additive way in the A549, but not in the tubulin-mutated, patupilone-resistant A549.EpoB40 cells. A supra-additive tumor growth delay was induced by combined treatment in xenografts derived from A549 cells, but not in xenografts derived from A549.EpoB40 cells. Histological analysis revealed a significant decrease in tumor cell proliferation and microvessel density and a treatment-dependent increase or decrease in tumor hypoxia only in A549 xenografts.
Conclusions: Using a genetically defined patupilone-sensitive and resistant tumor model we here demonstrated that the major cytotoxic effect of the combined treatment modality of IR and patupilone is directed against the tumor cell compartment. The induced anti-angiogenic effect derives indirectly from the tumor cell.