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.