TOMUDEX (ZD1694) - A NOVEL THYMIDYLATE SYNTHASE INHIBITOR WITH CLINICAL ANTITUMOR-ACTIVITY IN A RANGE OF SOLID TUMORS

Citation
D. Cunningham et al., TOMUDEX (ZD1694) - A NOVEL THYMIDYLATE SYNTHASE INHIBITOR WITH CLINICAL ANTITUMOR-ACTIVITY IN A RANGE OF SOLID TUMORS, Annals of oncology, 7(2), 1996, pp. 179-182
Citations number
10
Categorie Soggetti
Oncology
Journal title
ISSN journal
09237534
Volume
7
Issue
2
Year of publication
1996
Pages
179 - 182
Database
ISI
SICI code
0923-7534(1996)7:2<179:T(-ANT>2.0.ZU;2-L
Abstract
Background: Anti-metabolites such as methotrexate (MTX) and 5-fluorour acil (5-FU) have been used clinically for many years. Although their e ffects are partly due to thymidylate synthase (TS) inhibition, they al so have non-specific, non TS effects on RNA and purine synthesis. Dire ct and specific TS inhibitors therefore presented an attractive resear ch target. Collaborative research between the Institute of Cancer Rese arch and Zeneca Pharmaceuticals led to the design of specific folate b ased quinazoline TS inhibitors. ZD1694 ('Tomudex'), the first of these drugs reaching advanced clinical development, is currently completing phase III studies. Design: Eight phase II trials were carried out usi ng 'Tomudex', 3.0 mg/m(2), given as a short 15-minute infusion 3-weekl y. Results: 'Tomudex' demonstrates activity in a range of tumour types , most notably advanced colorectal and breast cancer (objective respon se 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 an d tiredness or malaise. Mucositis/stomatitis, alopecia and skin toxici ty were notable for their low incidence and mild intensity. Conclusion s: 'Tomudex' represents the successful culmination of a rational drug design programme, and shows promise as a new cytotoxic for the treatme nt of colorectal cancer. Further studies in other tumour types are pla nned.