‘Tomudex’ (ZD1694) : A novel thymidylate synthase inhibitor with clinical antitumour activity in a range of solid tumours

Abstract

Anti-metabolites such as methotrexate (MTX) and 5-fluorouracil (5-FU) have been used clinically for many years. Although their effects are partly due to thymidylate synthase (TS) inhibition, they also have non-specific, non TS effects on RNA and purine synthesis. Direct and specific TS inhibitors therefore presented an attractive research target. Collaborative research between the Institute of Cancer Research and Zeneca Pharmaceuticals led to the design of specific folate based quinazoline TS inhibitors. ZD1694 ('Tomudex'), the first of these drugs reaching advanced clinical development, is currently completing phase III studies. Eight phase II trials were carried out using 'Tomudex', 3.0 mg/m2, given as a short 15-minute infusion 3-weekly. 'Tomudex' demonstrates activity in a range of tumour types, most notably advanced colorectal and breast cancer (objective response rate 26%) and has acceptable toxicity: the most common WHO grade 3 and 4 adverse events were self-limiting reversible increases in liver transaminases, transient leucopenia, diarrhoea, nausea and vomiting and tiredness or malaise. Mucositis/stomatitis, alopecia and skin toxicity were notable for their low incidence and mild intensity. 'Tomudex' represents the successful culmination of a rational drug design programme, and shows promise as a new cytotoxic for the treatment of colorectal cancer. Further studies in other tumour types are planned.