Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel

摘要: The clinical success of small-molecule vascular disrupting agents (VDAs) depends on their combination with conventional therapies. Scheduling and sequencing remain key issues in the design VDA–chemotherapy treatments. This study examined antitumour activity ZD6126, a microtubule destabilising VDA, paclitaxel (PTX), microtubule-stabilising cytotoxic drug, influence schedule sequence efficacy combination. Nude mice bearing MDA-MB-435 xenografts received weekly cycles ZD6126 (200 mg kg−1 i.p.) administered at different times before or after PTX (10, 20, 40 mg kg−1 i.v.). given 2 24 h showed no significant benefit, result that was attributed to protective effect against ZD6126-induced damage tumour necrosis, hallmark VDA activity. Paclitaxel counteracting reduced by distancing drug administrations, 72 h potentiated VDA's Schedules improved therapeutic activity, which paralleled VDA-induced increase cell proliferation viable tissue. yielded best response (50% tumours regressing). A single treatment followed administration sufficient achieve similar (57% remissions). These findings show schedule, timing are crucial determining ZD6126. Induction necrosis increased remaining tissue could be exploited as readouts optimise schedules maximise efficacy.