Abstract

Irinotecan (CPT-11) is one of several camptothecin analogues that are currently in clinical use or development as anticancer drugs. CPT-11 has shown clinical activity against a number of tumours including colorectal, lung and ovarian cancers and has been approved in the United States for use as a first- and second-line treatment against colorectal cancer. Together with oxaliplatin, it has considerably changed the therapeutic strategy against colorectal cancer. The dose-limiting toxicities of CPT-11 are myelosuppression and delayed diarrhoea. CPT-11 is actually considered to be a prodrug that is converted in vivo to the active metabolite to SN-38. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that CPT-11 and all its metabolites have smaller LUMO-HOMO energy differences, indicating they would be kinetically labile. The molecular surfaces of CPT-11 and two of its metabolites NPC and CPT are found to abound in electron-deficient regions so that the compounds can react readily with glutathione and nucleobases in DNA, thus causing depletion of glutathione and damage to DNA. Depletion of reduced form of glutathione may induce cellular toxicity by compromising the antioxidant status of the cell.


 Key words: Irinotecan, CPT-11, SN-38, colorectal cancer, toxicity, nucleophilic, molecular modelling