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

Springer Science and Business Media LLC - Tập 17 Số 4 - Trang 3672-3689
Yasuhiro Tsume1, Gordon L. Amidon2,3
1Department of Pharmaceutical Science, University of Michigan, Ann Arbor, MI 48109, USA
2College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, MI 48109 USA
3Pharmaceutical Sciences

Tóm tắt

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.

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Tài liệu tham khảo

Jockovich, 2005, Combretastatin A-4 prodrug in the treatment of a murine model of retinoblastoma, Invest. Ophthalmol. Vis. Sci., 46, 8, 10.1167/iovs.04-0751

Moody, 2004, Development of high affinity camptothecin-bombesin conjugates that have targeted cytotoxicity for bombesin receptor-containing tumor cells, J. Biol. Chem., 279, 23580, 10.1074/jbc.M401938200

Senter, 2001, Identification and activities of human carboxylesterases for the activation of CPT-11, a clinically approved anticancer drug, Bioconjug. Chem., 12, 1074, 10.1021/bc0155420

Bras, 2001, Comparative bioavailability of acyclovir from oral valacyclovir and acyclovir in patients treated for recurrent genital herpes simplex virus infection, Can. J. Clin. Pharmacol., 8, 207

Curran, 2001, Valganciclovi, Drugs, 61, 1145, 10.2165/00003495-200161080-00013

Linden, 2002, Validation of microdialysis sampling for oral availability studies by means of a new ganciclovir prodrug, Pharmacol. Toxicol., 90, 297, 10.1034/j.1600-0773.2002.900602.x

Lentz, 2004, Increased acyclovir oral bioavailability via a bile acid conjugate, Mol. Pharm., 1, 40, 10.1021/mp034010t

Song, 2005, Amino acid ester prodrugs of the anticancer agent gemcitabine: Synthesis, bioconversion, metabolic bioevasion, and hPEPT1-mediated transport, Mol. Pharm., 2, 157, 10.1021/mp049888e

Nielsen, 2001, Dipeptide model prodrugs for the intestinal oligopeptide transporter. Affinity for and transport via hPepT1 in the human intestinal Caco-2 cell line, J. Control. Release, 76, 129, 10.1016/S0168-3659(01)00427-8

Thomsen, 2003, Prodrugs of purine and pyrimidine analogues for the intestinal di/tri-peptide transporter PepT1: affinity for hPepT1 in Caco-2 cells, drug release in aqueous media and in vitro metabolism, J. Control. Release, 86, 279, 10.1016/S0168-3659(02)00413-3

Vabeno, 2004, Dipeptidomimetic ketomethylene isosteres as pro-moieties for drug transport via the human intestinal di-/tripeptide transporter hPEPT1: Design, synthesis, stability, and biological investigations, J. Med. Chem., 47, 4755, 10.1021/jm040780c

Grem, 2000, 5-Fluorouracil: Forty-plus and still ticking. A review of its preclinical and clinical development, Invest. New Drugs, 18, 299, 10.1023/A:1006416410198

Parker, 1990, Metabolism and mechanism of action of 5-fluorouracil, Pharmacol. Ther., 48, 381, 10.1016/0163-7258(90)90056-8

Willmore, 1993, Cytotoxic mechanisms of 5-fluoropyrimidines. Relationships with poly(ADP-ribose) polymerase activity, DNA strand breakage and incorporation into nucleic acids, Biochem. Pharmacol., 46, 205, 10.1016/0006-2952(93)90405-L

Laskin, 979, Basis for natural variation in sensitivity to 5-fluorouracil in mouse and human cells in culture, Cancer Res., 39, 383

Yamada, 1998, In vitro study on intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for meningeal dissemination of malignant brain tumors, J. Neurooncol., 37, 115, 10.1023/A:1005869226496

Birnie, 1963, In vitro synthesis of acidsoluble thymine compounds by human neoplastic tissues, Cancer Res., 23, 420

Bencharit, 2002, Structural insights into CPT-11 activation by mammalian carboxylesterases, Nat. Struct. Biol., 9, 337, 10.1038/nsb790

Oosterhoff, 2002, Secreted and tumour targeted human carboxylesterase for activation of irinotecan, Br. J. Cancer, 87, 659, 10.1038/sj.bjc.6600519

Wu, 2002, Irinotecan activation by human carboxylesterases in colorectal adenocarcinoma cells, Clin. Cancer Res., 8, 2696

Xu, 2002, Human carboxylesterase 2 is commonly expressed in tumor tissue and is correlated with activation of irinotecan, Clin. Cancer Res., 8, 2605

Harel, 2005, The 3D structure of the anticancer prodrug CPT-11 with Torpedo californica acetylcholinesterase rationalizes its inhibitory action on AChE and its hydrolysis by butyrylcholinesterase and carboxylesterase, Chem. Biol. Interact., 157–158, 153, 10.1016/j.cbi.2005.10.016

Harel, 2005, The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action, Mol. Pharmacol., 67, 1874, 10.1124/mol.104.009944

Kondoh, 2003, A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer independently from the cathepsin D gene, Breast Cancer Res. Treat., 78, 37, 10.1023/A:1022149226430

Steinfeld, 2000, Prolactin up-regulates cathepsin B and D expression in minor salivary glands of patients with Sjogren’s syndrome, Lab. Invest., 80, 1711, 10.1038/labinvest.3780181

Skrzydlewska, 2005, Evaluation of serum cathepsin B and D in relation to clinicopathological staging of colorectal cancer, World J. Gastroenterol., 11, 4225, 10.3748/wjg.v11.i27.4225

Dumartin, 2011, AGR2 is a novel surface antigen that promotes the dissemination of pancreatic cancer cells through regulation of cathepsins B and D, Cancer Res., 71, 7091, 10.1158/0008-5472.CAN-11-1367

Whiteman, 2007, The role of S100P in the invasion of pancreatic cancer cells is mediated through cytoskeletal changes and regulation of cathepsin D, Cancer Res., 67, 8633, 10.1158/0008-5472.CAN-07-0545

Chauhan, 1991, Expression of cathepsin L in human tumors, Cancer Res., 51, 1478

Koblinski, 2000, Unraveling the role of proteases in cancer, Clin. Chim. Acta, 291, 113, 10.1016/S0009-8981(99)00224-7

Rochefort, 1999, Cathepsin D in cancer metastasis: A protease and a ligand, Apmis, 107, 86, 10.1111/j.1699-0463.1999.tb01530.x

Turk, 2002, Apoptotic pathways: involvement of lysosomal proteases, Biol. Chem., 383, 1035, 10.1515/BC.2002.112

Shen, 2004, Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry, Cancer Res., 64, 9018, 10.1158/0008-5472.CAN-04-3262

Abbott, 2010, Reevaluating cathepsin D as a biomarker for breast cancer: serum activity levels versus histopathology, Cancer Biol. Ther., 9, 23, 10.4161/cbt.9.1.10378

Baurain, 1980, Amino acid and dipeptide derivatives of daunorubicin. 2. Cellular pharmacology and antitumor activity on L1210 leukemic cells in vitro and in vivo, J. Med. Chem., 23, 1171, 10.1021/jm00185a004

Briozzo, 1988, In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells, Cancer Res., 48, 3688

Keppler, 1988, Immunohistochemical and biochemical study of a cathepsin B-like proteinase in human colonic cancers, Cancer Res., 48, 6855

Maciewicz, 1989, Immunodetection of cathepsins B and L present in and secreted from human pre-malignant and malignant colorectal tumour cell lines, Int. J. Cancer, 43, 478, 10.1002/ijc.2910430323

Masquelier, 1980, Amino acid and dipeptide derivatives of daunorubicin. 1. Synthesis, physicochemical properties, and lysosomal digestion, J. Med. Chem., 23, 1166, 10.1021/jm00185a003

Breistol, 1998, The antitumour activity of the prodrug N-L--leucyl-doxorubicin and its parent compound doxorubicin in human tumour xenografts, Eur. J. Cancer, 34, 1602, 10.1016/S0959-8049(98)00152-X

Quinney, 2005, Hydrolysis of capecitabine to 5'-deoxy-5-fluorocytidine by human carboxylesterases and inhibition by loperamide, J. Pharmacol. Exp. Ther., 313, 1011, 10.1124/jpet.104.081265

Schuller, 2000, Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients, Cancer Chemother. Pharmacol., 45, 291, 10.1007/s002800050043

Tsukamoto, 2001, Investigation of 5-FU disposition after oral administration of capecitabine, a triple-prodrug of 5-FU, using a physiologically based pharmacokinetic model in a human cancer xenograft model: Comparison of the simulated 5-FU exposures in the tumour tissue between human and xenograft model, Biopharm. Drug Dispos., 22, 1, 10.1002/bdd.250

Hu, 1989, Use of the peptide carrier system to improve the intestinal absorption of L-alpha-methyldopa: Carrier kinetics, intestinal permeabilities,and in vitro hydrolysis of dipeptidyl derivatives of L--alpha-methyldopa, Pharm. Res., 6, 66, 10.1023/A:1015855820488

Han, 1998, 5'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter, Pharm. Res., 15, 1154, 10.1023/A:1011919319810

Landowski, 2005, Floxuridine amino acid ester prodrugs: enhancing Caco-2 permeability and resistance to glycosidic bond metabolism, Pharm. Res., 22, 1510, 10.1007/s11095-005-6156-9

Landowski, 2005, Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs, Mol. Cancer Ther., 4, 659, 10.1158/1535-7163.MCT-04-0290

Lorenzi, 2005, Amino acid ester prodrugs of 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole enhance metabolic stability in vitro and in vivo, J. Pharmacol. Exp. Ther., 314, 883, 10.1124/jpet.104.082412

Tsume, 2008, Enhanced cancer cell growth inhibition by dipeptide prodrugs of floxuridine: Increased transporter affinity and metabolic stability, Mol. Pharm., 5, 717, 10.1021/mp800008c

Tsume, 2008, Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters, Molecules, 13, 1441, 10.3390/molecules13071441

Vig, 2003, Amino acid ester prodrugs of floxuridine: Synthesis and effects of structure, stereochemistry, and site of esterification on the rate of hydrolysis, Pharm. Res., 20, 1381, 10.1023/A:1025745824632

Berg, 1995, Physiological functions of endosomal proteolysis, Biochem. J., 307, 313, 10.1042/bj3070313

Claus, 1998, Lysosomal enzyme trafficking between phagosomes, endosomes, and lysosomes in J774 macrophages. Enrichment of cathepsin H in early endosomes, J. Biol. Chem., 273, 9842, 10.1074/jbc.273.16.9842

Kageshita, 1995, Biochemical and immunohistochemical analysis of cathepsins B, H, L and D in human melanocytic tumour, Arch. Dermatol. Res., 287, 266, 10.1007/BF01105077

Li, 2004, Increased expression and translocation of lysosomal cathepsins contribute to macrophage apoptosis in atherogenesis, Ann. NY Acad. Sci., 1030, 427, 10.1196/annals.1329.053

Roberg, 1998, Oxidative stress causes relocation of the lysosomal enzyme cathepsin D with ensuing apoptosis in neonatal rat cardiomyocytes, Am. J. Pathol., 152, 1151

Sameni, 1995, Cathepsin B and D are localized at the surface of human breast cancer cells, Pathol. Oncol. Res., 1, 43, 10.1007/BF02893583

Gronborg, 2006, Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach, Mol. Cell. Proteomics, 5, 157, 10.1074/mcp.M500178-MCP200

Reid, 1986, Immunolocalization of cathepsin D in normal and neoplastic human tissues, J. Clin. Pathol., 39, 1323, 10.1136/jcp.39.12.1323

Meyer, 2010, Human and viral nucleoside/nucleotide kinases involved in antiviral drug activation: Structural and catalytic properties, Antivir. Res., 86, 101, 10.1016/j.antiviral.2010.02.001

Kohchi, 2007, Design and synthesis of novel prodrugs of 2'-deoxy-2'-methylidenecytidine activated by membrane dipeptidase overexpressed in tumor tissues, Bioorg. Med. Chem. Lett., 17, 2241, 10.1016/j.bmcl.2007.01.066

Cohen, 2010, Enzymatic activation of a matrix metalloproteinase inhibitor, Chem. Commun. (Camb), 46, 1241, 10.1039/b923302d

Cohen, 2010, Hydrogen peroxide activated matrix metalloproteinase inhibitors: A prodrug approach, Angew. Chem. Int. Ed. Engl., 49, 6795, 10.1002/anie.201003819

Tabata, 2004, Identification of the cytosolic carboxylesterase catalyzing the 5'-deoxy-5-fluorocytidine formation from capecitabine in human liver, Drug Metab. Dispos., 32, 1103, 10.1124/dmd.104.000554

Alevizos, 2001, Oral cancer in vivo gene expression profiling assisted by laser capture microdissection and microarray analysis, Oncogene, 20, 6196, 10.1038/sj.onc.1204685

Elie, 2010, Identification and pre-clinical testing of a reversible cathepsin protease inhibitor reveals anti-tumor efficacy in a pancreatic cancer model, Biochimie, 92, 1618, 10.1016/j.biochi.2010.04.023

Nagler, 2004, Up-regulation of cathepsin X in prostate cancer and prostatic intraepithelial neoplasia, Prostate, 60, 109, 10.1002/pros.20046

Turk, 2002, Lysosomal cathepsins: structure, role in antigen processing and presentation, and cancer, Adv. Enzyme Regul., 42, 285, 10.1016/S0065-2571(01)00034-6

Devetzi, 2009, Cathepsin B protein levels in endometrial cancer: Potential value as a tumour biomarker, Gynecol. Oncol., 112, 531, 10.1016/j.ygyno.2008.10.030

Lah, 2010, Toward understanding recurrent meningioma: the potential role of lysosomal cysteine proteases and their inhibitors, J. Neurosurg., 112, 940, 10.3171/2009.7.JNS081729

Szumilo, 2009, Expression of syndecan-1 and cathepsins D and K in advanced esophageal squamous cell carcinoma, Folia Histochem. Cytobiol., 47, 571

Linebaugh, 1999, Exocytosis of active cathepsin B enzyme activity at pH 7.0, inhibition and molecular mass, Eur. J. Biochem., 264, 100, 10.1046/j.1432-1327.1999.00582.x

Pohl, 1987, Chromophoric and fluorophoric peptide substrates cleaved through the dipeptidyl carboxypeptidase activity of cathepsin B, Anal. Biochem., 165, 96, 10.1016/0003-2697(87)90205-3

Polgar, 1987, Dissociation of ionizing groups in the binding cleft inversely controls the endo- and exopeptidase activities of cathepsin B, J. Biol. Chem., 262, 14448, 10.1016/S0021-9258(18)47815-5

Ju, 1998, Upregulation of cathepsin D expression in the dedifferentiating salamander limb regenerates and enhancement of its expression by retinoic acid, Wound Repair Regen., 6, 349, 10.1046/j.1524-475X.1998.60410.x

Offermann, 1983, Action of cathepsin D on fructose-1,6-bisphosphate aldolase, Biochem. J., 211, 529, 10.1042/bj2110529

Hulkower, 2000, Fluorescent microplate assay for cancer cell-associated cathepsin B, Eur. J. Biochem., 267, 4165, 10.1046/j.1432-1327.2000.01458.x

Carvelli, 2010, Castration induces changes in the cation-dependent mannose-6-phosphate receptor in rat epididymis: Possible implications in secretion of lysosomal enzymes, J. Cell. Biochem., 110, 1101, 10.1002/jcb.22622

Landowski, 2006, Nucleoside ester prodrug substrate specificity of liver carboxylesterase, J. Pharmacol. Exp. Ther., 316, 572, 10.1124/jpet.105.092726

Murray, 1994, The aminopeptidase activity in the human T-cell lymphoma line (Jurkat) is not at the cell surface and is not aminopeptidase N (CD-13), Biochem. J., 298, 353, 10.1042/bj2980353

Landowski, 2004, Transporter and ion channel gene expression after Caco-2 cell differentiation using 2 different microarray technologies, AAPS J., 6, e21, 10.1208/aapsj060321

Sun, 2002, Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs, Pharm. Res., 19, 1400, 10.1023/A:1020483911355