Researchers at St. Jude have identified a rabbit and a human carboxylesterase with the capacity to efficiently cleave esterase linkages and thereby modulate prodrug metabolism. These carboxylesterases can be used to promote the conversion of prodrugs containing such linkages into drugs. For example, the prodrug CPT-11 can be converted by these carboxylesterases into its active form, SN-38, a topoisomerase I inhibitor used as a chemotherapeutic drug. In another aspect of this invention, a screening assay is provided for identifying prodrugs that are activated by these carboxylesterases.
Prodrug, topoisomerase I inhibitor, carboxylesterase
Granted Patents or Published Applications
U.S. Patent Nos. 6,800,483; 7,018,631 and 7,452,717; Australian Patent No. 755251
Related Scientific References
Wadkins, RM, et al., "Structural Constraints Affect the Metabolism of 7-Ethyl-10-[4-1(1-peperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) by Carboxylesterases" Molecular Pharmacology 60:355-362 (2001);
Meck MM, et al, "A Virus-Directed Enzyme Produg Therapy Approach to Purging Neuroblastoma Cells from Hematopoietic Cells Using Adenovirus Encoding Rabbit Carboxylesterase and CPT-11" Cancer Res. 61(13):5083-5089 (2001);
Wierdl, M., et al., "Sensitization of Human Tumor Cells to CPT-11 Via Adenoviral-Mediated Delivery of a Rabbit Liver Carboxylesterase." Cancer Res. 61(13):5078-5082 (2001);
Danks, MK, et al, "Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy" Clin Cancer Res. 5(4):917-924 (1999).
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