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The Feasibility of Enzyme Targeted Activation for Amino Acid/Dipeptide Monoester Prodrugs of Floxuridine; Cathepsin D as a Potential Targeted Enzyme

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Department of Pharmaceutical Science, University of Michigan, Ann Arbor, MI 48109, USA
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College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA
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Author to whom correspondence should be addressed.
Molecules 2012, 17(4), 3672-3689; https://doi.org/10.3390/molecules17043672
Received: 31 January 2012 / Revised: 14 March 2012 / Accepted: 21 March 2012 / Published: 26 March 2012
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 enyzmes. 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. View Full-Text
Keywords: prodrugs; Capan-2 cell; cathepsin; enzymatic activation; cell proliferation assay prodrugs; Capan-2 cell; cathepsin; enzymatic activation; cell proliferation assay
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Tsume, Y.; Amidon, G.L. The Feasibility of Enzyme Targeted Activation for Amino Acid/Dipeptide Monoester Prodrugs of Floxuridine; Cathepsin D as a Potential Targeted Enzyme. Molecules 2012, 17, 3672-3689.

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