In the early sixties of the last century, camptothecin (CPT) was isolated from the Chinese plant Camptotheca acuminata (Nyssaceae family), and was found to be a very potent antitumor agent in vitro. However, its clinical development was hindered by a relatively limited clinical activity and severe and unpredictable toxicities, most problematic being hemorrhagic cystitis and enteritis. These turned out to be partially related to the poor hydrophilicity of the drug and the initial administration of camptothecin in the inactive carboxylate form. Once the mechanism of action of camptothecin was discovered, there was renewed interest in the drug. Eff orts were made to develop water-soluble camptothecin analogues with improved antitumor activity and decreased toxicity. Irinotecan, also known as CPT-11, was developed as a water-soluble prodrug of SN-38, a very potent camptothecin analogue, which has a 100-1000 fold higher cytotoxic activity in vitro than the parent compound. Camptothecins, including irinotecan and SN-38, inhibit the enzyme topoisomerase-I by binding to it and forming a stable complex between topoisomerase-I and DNA. This induces single-strand breaks in chromosomal DNA, ultimately leading to cytotoxicity and apoptosis.

J. Verweij (Jaap)
Erasmus University Rotterdam
Erasmus MC Rotterdam, Pfizer bv, Merck Sharp & Dohme BV, Janssen-Cilag B.V., Amgen B.V., Boehringer Ingelheim, Novartis Oncology
Erasmus MC: University Medical Center Rotterdam

van der Bol, J.M. (2011, June 17). Personalized Irinotecan Treatment: the patient matters. Erasmus University Rotterdam. Retrieved from