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