%0 Journal Article %A PAVLA PLAČKOVÁ %A NELA ROZUMOVÁ %A HUBERT HŘEBABECKÝ %A MICHAL ŠÁLA %A RADIM NENCKA %A TOMÁŠ ELBERT %A ALEXANDRA DVOŘÁKOVÁ %A IVAN VOTRUBA %A HELENA MERTLÍKOVÁ-KAISEROVÁ %T 9-Norbornyl-6-chloropurine Is a Novel Antileukemic Compound Interacting with Cellular GSH %D 2013 %J Anticancer Research %P 3163-3168 %V 33 %N 8 %X Aim: 6-Chloropurines substituted at position 9 with bicyclic skeletons represent promising chemotherapeutic agents. We explored the metabolism and membrane transport of 9-norbornyl-6-chloropurine (NCP) aiming to understand its mechanism of action. Materials and Methods: The metabolism of NCP was studied in vitro in whole cells (CCRF-CEM), cellular extracts, subcellular fractions and purified enzymes. Transport experiments were conducted in Caco-2 cell monolayers. Results: Three metabolites were identified, a glutathione conjugate (NCP-GS), NCP-cysteinylglycine and NCP-cysteine. Both glutathione-S-transferase inhibition and glutathione (GSH) depletion prevented metabolite formation and increased the cytotoxicity of NCP. Transepithelial transport (Caco-2) indicated good permeability, with Papp (12.6±0.3) ×10−5 cm/s. Importantly, the drug induced glutathione depletion in treated cells and affected the activity of several GSH-dependent enzymes. Conclusion: The novel nucleoside analog NCP represents a promising orally available antileukemic agent, acting through lowering of GSH levels in tumor cells. %U https://ar.iiarjournals.org/content/anticanres/33/8/3163.full.pdf