The antitumour activity of ZD9331, a non-polyglutamatable quinazoline thymidylate synthase inhibitor

Abstract

ZD9331 is a very potent, quinazoline-based TS inhibitor, which although having structural similarities with classical TS inhibitors, has biochemical features in common with the non-classical inhibitors of this enzyme. Water- solubility, transport into the cell via the RFC but lack of intracellular polyglutamation give this drug its hybrid properties. The 150-fold improvement in TS inhibitory activity over Tomudex predominantly accounts for equivalent cytotoxic activity, when given by continuous exposure. The drug exerts its effect only while it is present extracellularly. This feature, together with rapid plasma clearance in mice, should give the control over inhibition of DNA synthesis desired from this class of agent. ZD9331 is active in a Tomudex-resistant cell line unable to polyglutamate classical antifolates. Pre-clinical in vivo studies are ongoing to define more closely the toxicology and administration protocols appropriate to ZD9331.