Title:Namitecan: a Hydrophilic Camptothecin with a Promising Preclinical Profile
Volume: 19
Issue: 21
Author(s): G. L. Beretta, V. Zuco, M. De Cesare, P. Perego and N. Zaffaroni
Affiliation:
Keywords:
Antitumor therapy, Camptothecins, Cellular pharmacology, Clinical studies, Drug resistance, Gimatecan, Namitecan, 7-
oxyiminomethyl derivatives, Topoisomerase I, Tumor cells
Abstract: Camptothecins are still among the most widely prescribed and effective anticancer drugs. Unfortunately, important drawbacks
including water insolubility, lactone instability, reversibility of the drug–target interaction, drug resistance and toxicity are responsible for
treatment failure and often require suspension of the drug administration itself. In order to overcome such drawbacks, several options in
chemical manipulation of natural camptothecin have been explored, and effective compounds have been identified in a novel series of 7-
oxyiminomethyl derivatives. Among the compounds of this series, the hydrophilic derivative namitecan (7 (2-aminoethoxy) iminomethyl
camptothecin) has been selected for further development. The relevant features of namitecan are: 1) marked cytotoxic potency - likely
related to multiple factors, including i) a potent inhibition of topoisomerase I, ii) a persistent stabilization of the cleavable complex, iii) an
increased intracellular accumulation, and iv) a peculiar subcellular localization; 2) enhanced lactone stability and favorable
pharmacokinetics; 3) remarkable antitumor efficacy in a large panel of human tumor xenografts (including tumor models relatively
resistant to topotecan and irinotecan), particularly on squamous cell carcinomas. The clinical development of namitecan is currently
ongoing. Namitecan exhibited an acceptable toxicity profile, with neutropenia being the dose-limiting toxic effect, and clinical benefit
was appreciable in patients with different tumor types, particularly bladder and endometrium carcinomas. In this article, we review the
relevant features of namitecan, with particular reference to its advantages compared with the two analogues (topotecan and irinotecan)
approved for clinical use.
