Schedule dependence of combretastatin A4 phosphate in transplanted and spontaneous tumour models

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Abstract
Tubulin depolymerizing drugs that selectively disrupt tumour-associated vasculature have recently been identified. The lead drug in this class, combretastatin A4 phosphate (CA4P), has just completed Phase I clinical trial. Previous studies have focussed on the effects of single drug doses and have demonstrated little or no retardation of tumour growth when CA4P is used alone, but significant benefit when it is combined with conventional treatment. We have investigated the effects of multiple daily or twice daily dosing with CA4P on the vascular function, cell survival and growth of syngeneic and spontaneous breast cancers in mice. In both transplanted and spontaneous tumours significant growth retardation is observed if CA4P is administered daily (10 doses x 50 mg/kg), whereas no significant effects are seen if the same total dose (500 mg/kg) is administered as a single bolus injection. This effect is attributed, at least in part, to anti-proliferative effects on the tumour and endothelial cells, which retard the revascularisation and repopulation of the tumour core that is initially necrosed by the drug treatment. Further investigation of dose scheduling showed that the initial anti-vascular effects of CA4P are enhanced by administering the drug in 2 equal doses separated between 2 and 6 hr. The twice daily dosing schedule (25 mg/kg twice a day) produced increased growth retardation compared to the 50 mg/kg once a day schedule in the transplanted CaNT tumour. It did not do so in the spontaneous T138 tumour model. These studies indicate that the potential anti-tumour activity of CA4P when used as a single agent in clinical trials may be enhanced when used in multiple dose schedules.