title: The feasibility of enzyme targeted activation for amino acid/dipeptide monoester prodrugs of floxuridine; cathepsin D as a potential targeted enzyme.
abstract: The improvement of therapeutic efficacy for cancer agents has been a big challenge which includes the increase of tumor selectivity and the reduction of adverse effects at non-tumor sites. In order to achieve those goals, prodrug approaches have been extensively investigated. In this report, the potential activation enzymes for 5'-amino acid/dipeptide monoester floxuridine prodrugs in pancreatic cancer cells were selected and the feasibility of enzyme specific activation of prodrugs was evaluated. All prodrugs exhibited the range of 3.0-105.7 min of half life in Capan-2 cell homogenate with the presence and the absence of selective enzyme inhibitors. 5'-O-L-Phenylalanyl-L-tyrosyl-floxuridine exhibited longer half life only with the presence of pepstatin A. Human cathepsin B and D selectively hydrolized 5'-O-L-phenylalanyl-L-tyrosylfloxuridine and 5'-O-L-phenylalanyl-L-glycylfloxuridine compared to the other tested prodrugs. The wide range of growth inhibitory effect by floxuridine prodrugs in Capan-2 cells was observed due to the different affinities of prodrug promoieties to enzymes. In conclusion, it is feasible to design prodrugs which are activated by specific enzymes. Cathepsin D might be a good candidate as a target enzyme for prodrug activation and 5'-O-L-phenylalanyl-L-tyrosylfloxuridine may be the best candidate among the tested floxuridine prodrugs.
authors.affiliation: Department of Pharmaceutical Science, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsume
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D002401:Cathepsin B / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000378:metabolism; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D005467:Floxuridine / Q000378:metabolism* / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000964:Antimetabolites, Antineoplastic; D004151:Dipeptides; D011355:Prodrugs; D005467:Floxuridine; D002401:Cathepsin B; D002402:Cathepsin D