Perspectives in camptothecin development

Abstract

DNA topoisomerase I is recognised as a useful target for antitumour therapy. Camptothecin is the prototype topoisomerase I specific inhibitor. The impressive antitumour activity of camptothecins in preclinical models and the clinical success of topotecan and irinotecan have stimulated intense research activities and various strategies to identify novel compounds and to overcome the main limitations of the camptothecin molecule (i.e., instability of the lactone ring and reversibility of drug–target interaction). The original water-insolubility problem of the naturally occurring compound has been overcome with the development of various water-soluble analogues, for intravenous administration. Some of these compounds fulfilled requirements for clinical development. The approaches to improve the antitumour efficacy of agents of this class rely on quite different principles. Some involve the development of prodrugs and delivery systems. Recently, novel series of lipophilic analogues have been described. These share some common features, including oral bioavailability, ability to cross the blood–brain barrier, an increased stability of the lactone ring and potent topoisomerase I inhibition. Several derivatives are still in preclinical development and some of these novel agents are presently undergoing clinical evaluation. This review will focus on the progress currently being made on various approaches in this field.

• antitumour chemotherapy
• camptothecins (CPTs)
• topoisomerase I inhibitors