Suppression of Tumor Growth in Mice by Rationally Designed Pseudopeptide Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

Neoplasia (United States)

Volumn 17, Issue 1, 2015, Pages 43-54

  Jackson, Kenneth W ^a   Christiansen, Victoria J ^a   Yadav, Vivek R ^b   Silasi Mansat, Robert ^c   Lupu, Florea ^c   Awasthi, Vibhudutta ^b   Zhang, Roy R ^a   McKee, Patrick A ^a  

^a UNIVERSITY OF OKLAHOMA COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER   (United States)

^c OKLAHOMA MEDICAL RESEARCH FOUNDATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7 N (4 HYDROXYPHENYL)MITOMYCIN C; ANTINEOPLASTIC AGENT; FIBROBLAST ACTIVATION PROTEIN; J 94; PROLYL ENDOPEPTIDASE; PROLYL ENDOPEPTIDASE INHIBITOR; SODIUM CHLORIDE; UNCLASSIFIED DRUG; GELATINASE; MEMBRANE PROTEIN; PEPTIDE; PROTEINASE INHIBITOR; SEPRASE; SERINE PROTEINASE;

ANIMAL BEHAVIOR; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; APOPTOSIS; ARTICLE; BIOACCUMULATION; BODY WEIGHT; COLON CANCER; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME INHIBITION; GASTROINTESTINAL TRACT FUNCTION; GROWTH INHIBITION; HCT116 CELL LINE; HISTOPATHOLOGY; HUMAN; HUMAN CELL; IMMUNOHISTOCHEMISTRY; LUNG CANCER; MALE; MICROVASCULATURE; MOUSE; MOUSE MODEL; NONHUMAN; PRIORITY JOURNAL; TUMOR MICROENVIRONMENT; TUMOR XENOGRAFT; AMINO ACID SEQUENCE; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG DESIGN; DRUG EFFECTS; DRUG SCREENING; EXPERIMENTAL NEOPLASM; METABOLISM; MOLECULAR GENETICS; NEOPLASMS; PATHOLOGY; TUMOR CELL LINE; TUMOR VOLUME;

AMINO ACID SEQUENCE; ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; DRUG DESIGN; GELATINASES; HUMANS; MALE; MEMBRANE PROTEINS; MICE; MOLECULAR SEQUENCE DATA; NEOPLASMS; NEOPLASMS, EXPERIMENTAL; PEPTIDES; PROTEASE INHIBITORS; SERINE ENDOPEPTIDASES; TUMOR BURDEN; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84964694641     PISSN: 15228002     EISSN: 14765586     Source Type: Journal    
DOI: 10.1016/j.neo.2014.11.002     Document Type: Article

References (82)

1. [1] Connolly, J, Schnitt, S, Wang, H, Dvorak, A, Dvorak, H, Principles of Cancer Pathology. Bast, RJ, Kufe, D, Pollock, R, Welchselbaum, R, Holland, J, Frei, E, (eds.) Holland-Frei Cancer Medicine, 2000.
2. [2] Folkman, J, What is the evidence that tumors are angiogenesis dependent?. J Natl Cancer Inst 82 (1990), 4–6.
3. [3] Park, JE, Lenter, MC, Zimmermann, RN, Garin-Chesa, P, Old, LJ, Rettig, WJ, Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem 274 (1999), 36505–36512.
4. [4] Garin-Chesa, P, Old, LJ, Rettig, WJ, Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci U S A 87 (1990), 7235–7239.
5. [5] Cheng, JD, Dunbrack, RL Jr., Valianou, M, Rogatko, A, Alpaugh, RK, Weiner, LM, Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res 62 (2002), 4767–4772.
6. [6] Puré, E, The road to integrative cancer therapies: emergence of a tumor-associated fibroblast protease as a potential therapeutic target in cancer. Expert Opin Ther Targets 13 (2009), 967–973.
7. [7] Hayward, SW, Preclinical assessment of fibroblast activation protein as a target for antitumor therapy. Future Oncol 6 (2010), 347–349.
8. [8] Brennen, WN, Isaacs, JT, Denmeade, SR, Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther 11 (2012), 257–266.
9. [9] Tchou, J, Conejo-Garcia, J, Targeting the tumor stroma as a novel treatment strategy for breast cancer: shifting from the neoplastic cell-centric to a stroma-centric paradigm. Adv Pharmacol 65 (2012), 45–61.
10. [10] Christiansen, VJ, Jackson, KW, Lee, KN, Downs, TD, McKee, PA, Targeting inhibition of fibroblast activation protein-α and prolyl oligopeptidase activities on cells common to metastatic tumor microenvironments. Neoplasia 15 (2013), 348–358.
11. [11] Cheng, JD, Weiner, LM, Tumors and their microenvironments: tilling the soil. Commentary re: A. M. Scott et al., A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin. Cancer Res., 9: 1639-1647, 2003. Clin Cancer Res 9 (2003), 1590–1595.
12. [12] Christiansen, VJ, Jackson, KW, Lee, KN, McKee, PA, Effect of fibroblast activation protein and alpha2-antiplasmin cleaving enzyme on collagen types I, III, and IV. Arch Biochem Biophys 457 (2007), 177–186.
13. [13] Liu, R, Li, H, Liu, L, Yu, J, Ren, X, Fibroblast activation protein: A potential therapeutic target in cancer. Cancer Biol Ther 13 (2012), 123–129.
14. [14] Lee, HO, Mullins, SR, Franco-Barraza, J, Valianou, M, Cukierman, E, Cheng, JD, FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer, 11, 2011, 245.
15. [15] Jacob, M, Chang, L, Pure, E, Fibroblast activation protein in remodeling tissues. Curr Mol Med 12 (2012), 1220–1243.
16. [16] Liao, D, Luo, Y, Markowitz, D, Xiang, R, Reisfeld, RA, Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One, 4, 2009, e7965.
17. [17] Kraman, M, Bambrough, PJ, Arnold, JN, Roberts, EW, Magiera, L, Jones, JO, Gopinathan, A, Tuveson, DA, Fearon, DT, Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330 (2010), 827–830.
18. [18] Tran, E, Chinnasamy, D, Yu, Z, Morgan, RA, Lee, CC, Restifo, NP, Rosenberg, SA, Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med 210 (2013), 1125–1135.
19. [19] Roberts, EW, Deonarine, A, Jones, JO, Denton, AE, Feig, C, Lyons, SK, Espeli, M, Kraman, M, McKenna, B, Wells, RJ, et al. Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia. J Exp Med 210 (2013), 1137–1151.
20. [20] Kakarla, S, Chow, KK, Mata, M, Shaffer, DR, Song, XT, Wu, MF, Liu, H, Wang, LL, Rowley, DR, Pfizenmaier, K, et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther 21 (2013), 1611–1620.
21. [21] Reisfeld, RA, The tumor microenvironment: a target for combination therapy of breast cancer. Crit Rev Oncog 18 (2013), 115–133.
22. [22] Feig, C, Jones, JO, Kraman, M, Wells, RJ, Deonarine, A, Chan, DS, Connell, CM, Roberts, EW, Zhao, Q, Caballero, OL, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 110 (2013), 20212–20217.
23. [23] Huang, Y, Wang, S, Kelly, T, Seprase promotes rapid tumor growth and increased microvessel density in a mouse model of human breast cancer. Cancer Res 64 (2004), 2712–2716.
24. [24] Santos, AM, Jung, J, Aziz, N, Kissil, JL, Puré, E, Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest 119 (2009), 3613–3625.
25. [25] Zimmerlin, L, Donnenberg, VS, Donnenberg, AD, Pericytes: a universal adult tissue stem cell?. Cytometry A 81 (2012), 12–14.
26. [26] Jung, YD, Ahmad, SA, Liu, W, Reinmuth, N, Parikh, A, Stoeltzing, O, Fan, F, Ellis, LM, The role of the microenvironment and intercellular cross-talk in tumor angiogenesis. Semin Cancer Biol 12 (2002), 105–112.
27. [27] Cheng, JD, Valianou, M, Canutescu, AA, Jaffe, EK, Lee, HO, Wang, H, Lai, JH, Bachovchin, WW, Weiner, LM, Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth. Mol Cancer Ther 4 (2005), 351–360.
28. [28] Sedo, A, Krepela, E, Kasafirek, E, Dipeptidyl peptidase IV, prolyl endopeptidase and cathepsin B activities in primary human lung tumors and lung parenchyma. J Cancer Res Clin Oncol 117 (1991), 249–253.
29. [29] Goossens, F, De Meester, I, Vanhoof, G, Scharpé, S, Distribution of prolyl oligopeptidase in human peripheral tissues and body fluids. Eur J Clin Chem Clin Biochem 34 (1996), 17–22.
30. [30] Larrinaga, G, Perez, I, Blanco, L, Lopez, JI, Andrés, L, Etxezarraga, C, Santaolalla, F, Zabala, A, Varona, A, Irazusta, J, Increased prolyl endopeptidase activity in human neoplasia. Regul Pept 163 (2010), 102–106.
31. [31] Myöhänen, TT, Pyykkö, E, Männistö, PT, Carpen, O, Distribution of prolyl oligopeptidase in human peripheral tissues and in ovarian and colorectal tumors. J Histochem Cytochem 60 (2012), 706–715.
32. [32] Larrinaga, G, Perez, I, Blanco, L, Sanz, B, Errarte, P, Beitia, M, Etxezarraga, MC, Loizate, A, Gil, J, Irazusta, J, et al. Prolyl endopeptidase activity is correlated with colorectal cancer prognosis. Int J Med Sci 11 (2014), 199–208.
33. [33] Liu, JM, Garcia-Alvarez, MC, Bignon, J, Kusinski, M, Kuzdak, K, Riches, A, Wdzieczak-Bakala, J, Overexpression of the natural tetrapeptide acetyl-N-ser-asp-lys-pro derived from thymosin β4 in neoplastic diseases. Ann N Y Acad Sci 1194 (2010), 53–59.
34. 4 in tumor metastasis and angiogenesis. J Natl Cancer Inst 95 (2003), 1674–1680.
35. [35] Nemolato, S, Restivo, A, Cabras, T, Coni, P, Zorcolo, L, Orru, G, Fanari, M, Cau, F, Gerosa, C, Fanni, D, et al. Thymosin β-4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition. Cancer Biol Ther 13 (2012), 191–197.
36. [36] Kim, NS, Kang, YJ, Jo, JO, Kim, HY, Oh, YR, Kim, YO, Jung, MH, Ock, MS, Cha, HJ, Elevated expression of thymosin β4, vascular endothelial growth factor (VEGF), and hypoxia inducible factor (HIF)-1α in early-stage cervical cancers. Pathol Oncol Res 17 (2011), 493–502.
37. [37] Cavasin, MA, Rhaleb, NE, Yang, XP, Carretero, OA, Prolyl oligopeptidase is involved in release of the antifibrotic peptide Ac-SDKP. Hypertension 43 (2004), 1140–1145.
38. [38] Myohanen, TT, Tenorio-Laranga, J, Jokinen, B, Vazquez-Sanchez, R, Moreno-Baylach, MJ, Garcia-Horsman, JA, Mannisto, PT, Prolyl oligopeptidase induces angiogenesis both in vitro and in vivo in a novel regulatory manner. Br J Pharmacol 163 (2011), 1666–1678.
39. [39] Wang, D, Carretero, OA, Yang, XY, Rhaleb, NE, Liu, YH, Liao, TD, Yang, XP, N-acetyl-seryl-aspartyl-lysyl-proline stimulates angiogenesis in vitro and in vivo. Am J Physiol Heart Circ Physiol 287 (2004), H2099–H2105.
40. [40] Smart, N, Rossdeutsch, A, Riley, PR, Thymosin β4 and angiogenesis: modes of action and therapeutic potential. Angiogenesis 10 (2007), 229–241.
41. [41] Grant, DS, Rose, W, Yaen, C, Goldstein, A, Martinez, J, Kleinman, H, Thymosin beta4 enhances endothelial cell differentiation and angiogenesis. Angiogenesis 3 (1999), 125–135.
42. [42] Suzuki, K, Sakaguchi, M, Tanaka, S, Yoshimoto, T, Takaoka, M, Prolyl oligopeptidase inhibition-induced growth arrest of human gastric cancer cells. Biochem Biophys Res Commun 443 (2014), 91–96.
43. [43] Adams, S, Miller, GT, Jesson, MI, Watanabe, T, Jones, B, Wallner, BP, PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res 64 (2004), 5471–5480.
44. [44] Nemunaitis, J, Vukelja, SJ, Richards, D, Cunningham, C, Senzer, N, Nugent, J, Duncan, H, Jones, B, Haltom, E, Uprichard, MJ, Phase I trial of PT-100 (PT-100), a cytokine-inducing small molecule, following chemotherapy for solid tumor malignancy. Cancer Invest 24 (2006), 553–561.
45. [45] Narra, K, Lee, HO, Lerro, A, Valvardi, J, Azeez, O, Jesson, MI, Aziz, N, Jones, B, Cheng, JD, Inhibitors of the stromal protease fibroblast activation protein attenuate tumor growth in vivo. AACR Meeting Abstracts, 2006, 1029.
46. [46] Narra, K, Mullins, SR, Lee, HO, Strzemkowski-Brun, B, Magalong, K, Christiansen, VJ, McKee, PA, Egleston, B, Cohen, SJ, Weiner, LM, et al. Phase II trial of single agent Val-boroPro (Talabostat) inhibiting Fibroblast Activation Protein in patients with metastatic colorectal cancer. Cancer Biol Ther 6 (2007), 1691–1699.
47. [47] Walsh, MP, Duncan, B, Larabee, S, Krauss, A, Davis, JP, Cui, Y, Kim, SY, Guimond, M, Bachovchin, W, Fry, TJ, Val-boroPro accelerates T cell priming via modulation of dendritic cell trafficking resulting in complete regression of established murine tumors. PLoS One, 8, 2013, e58860.
48. [48] Kelly, T, Adams, J, Bachovchin, W, Barton, R, Campbell, S, Courts, S, Kennedy, C, Snow, R, Immunosuppressive boronic acid dipeptides: correlation between conformation and activity. J Am Chem Soc 115 (1993), 12637–12638.
49. [49] Lee, KN, Jackson, KW, Christiansen, VJ, Dolence, EK, McKee, PA, Enhancement of fibrinolysis by inhibiting enzymatic cleavage of precursor α2-antiplasmin. J Thromb Haemost 9 (2011), 987–996.
50. [50] Maes, M, Goossens, F, Scharpe, S, Calabrese, J, Desnyder, R, Meltzer, HY, Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs. Psychiatry Res 58 (1995), 217–225.
51. [51] Huang, Y, Simms, AE, Mazur, A, Wang, S, León, NR, Jones, B, Aziz, N, Kelly, T, Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions. Clin Exp Metastasis 28 (2011), 567–579.
52. [52] Kelly, T, Huang, Y, Simms, AE, Mazur, A, Fibroblast activation protein-α: a key modulator of the microenvironment in multiple pathologies. Int Rev Cell Mol Biol 297 (2012), 83–116.
53. [53] Cai, F, Li, Z, Wang, C, Xian, S, Xu, G, Peng, F, Wei, Y, Lu, Y, Short hairpin RNA targeting of fibroblast activation protein inhibits tumor growth and improves the tumor microenvironment in a mouse model. BMB Rep 46 (2013), 252–257.
54. [54] Xiao, Y, Chen, Y, Wen, J, Yan, W, Zhou, K, Cai, W, Thymosin β4: a potential molecular target for tumor therapy. Crit Rev Eukaryot Gene Expr 22 (2012), 109–116.
55. [55] Lee, KN, Jackson, KW, Terzyan, S, Christiansen, VJ, McKee, PA, Using substrate specificity of antiplasmin-cleaving enzyme for fibroblast activation protein inhibitor design. Biochemistry 48 (2009), 5149–5158.
56. [56] Gorrao, SS, Hemerly, JP, Lima, AR, Melo, RL, Szeltner, Z, Polgar, L, Juliano, MA, Juliano, L, Fluorescence resonance energy transfer (FRET) peptides and cycloretro-inverso peptides derived from bradykinin as substrates and inhibitors of prolyl oligopeptidase. Peptides 28 (2007), 2146–2154.
57. [57] Schneider, CA, Rasband, WS, Eliceiri, KW, NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9 (2012), 671–675.
58. [58] Van, ER, Lambeir, AM, Structure and function relationship in prolyl oligopeptidase. CNS Neurol Disord Drug Targets 10 (2011), 297–305.
59. [59] Goossens, F, De, MI, Vanhoof, G, Scharpé, S, A sensitive method for the assay of serum prolyl endopeptidase. Eur J Clin Chem Clin Biochem 30 (1992), 235–238.
60. [60] Tenorio-Laranga, J, Venäläinen, JI, Männistö, PT, García-Horsman, JA, Characterization of membrane-bound prolyl endopeptidase from brain. FEBS J 275 (2008), 4415–4427.
61. [61] Liu, JM, Kusinski, M, Ilic, V, Bignon, J, Hajem, N, Komorowski, J, Kuzdak, K, Stepien, H, Wdzieczak-Bakala, J, Overexpression of the angiogenic tetrapeptide AcSDKP in human malignant tumors. Anticancer Res 28 (2008), 2813–2817.
62. [62] Cavallo-Medved, D, Rudy, D, Blum, G, Bogyo, M, Caglic, D, Sloane, BF, Live-cell imaging demonstrates extracellular matrix degradation in association with active cathepsin B in caveolae of endothelial cells during tube formation. Exp Cell Res 315 (2009), 1234–1246.
63. [63] Newman, AC, Nakatsu, MN, Chou, W, Gershon, PD, Hughes, CC, The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation. Mol Biol Cell 22 (2011), 3791–3800.
64. [64] Fukumura, D, Jain, RK, Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res 74 (2007), 72–84.
65. [65] Noma, K, Smalley, KS, Lioni, M, Naomoto, Y, Tanaka, N, El-Deiry, W, King, AJ, Nakagawa, H, Herlyn, M, The essential role of fibroblasts in esophageal squamous cell carcinoma-induced angiogenesis. Gastroenterology 134 (2008), 1981–1993.
66. [66] Polgár, L, The prolyl oligopeptidase family. Cell Mol Life Sci 59 (2002), 349–362.
67. [67] García-Horsman, JA, Männistö, PT, Venäläinen, JI, On the role of prolyl oligopeptidase in health and disease. Neuropeptides 41 (2007), 1–24.
68. [68] Tenorio-Laranga, J, Männistö, PT, García-Horsman, JA, Hunting for peptide substrates of prolyl oligopeptidase: classical versus non-classical bioactive peptides. CNS Neurol Disord Drug Targets 10 (2011), 319–326.
69. [69] Myöhänen, TT, García-Horsman, JA, Tenorio-Laranga, J, Männistö, PT, Issues about the physiological functions of prolyl oligopeptidase based on its discordant spatial association with substrates and inconsistencies among mRNA, protein levels, and enzymatic activity. J Histochem Cytochem 57 (2009), 831–848.
70. [70] Cavasin, MA, Liao, TD, Yang, XP, Yang, JJ, Carretero, OA, Decreased endogenous levels of Ac-SDKP promote organ fibrosis. Hypertension 50 (2007), 130–136.
71. [71] Zuo, Y, Chun, B, Potthoff, SA, Kazi, N, Brolin, TJ, Orhan, D, Yang, HC, Ma, LJ, Kon, V, Myöhänen, T, et al. Thymosin β4 and its degradation product, Ac-SDKP, are novel reparative factors in renal fibrosis. Kidney Int 84 (2013), 1166–1175.
72. [72] Spector, I, Zilberstein, Y, Lavy, A, Nagler, A, Genin, O, Pines, M, Involvement of host stroma cells and tissue fibrosis in pancreatic tumor development in transgenic mice. PLoS One, 7, 2012, e41833.
73. [73] Rich, L, Whittaker, P, Collagen and picrosirius red staining: a polarized light assessment of fibrillar hue and spatial distribution. Braz J Morphol Sci 22 (2005), 97–104.
74. [74] Netti, PA, Berk, DA, Swartz, MA, Grodzinsky, AJ, Jain, RK, Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res 60 (2000), 2497–2503.
75. [75] Jansen, K, Heirbaut, L, Verkerk, R, Cheng, JD, Joossens, J, Cos, P, Maes, L, Lambeir, AM, De Meester, I, Augustyns, K, et al. Extended structure-activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP). J Med Chem 57 (2014), 3053–3074.
76. [76] Jo, JO, Kim, SR, Bae, MK, Kang, YJ, Ock, MS, Kleinman, HK, Cha, HJ, Thymosin β4 induces the expression of vascular endothelial growth factor (VEGF) in a hypoxia-inducible factor (HIF)-1α-dependent manner. Biochim Biophys Acta 1803 (2010), 1244–1251.
77. [77] Cooper, G, Transport of small molecules. The Cell: A Molecular Approach, 2000, Sinauer Associates, Sunderland, MA [www.ncbi.nlm.nih.gov/books/NBK9847/].
78. [78] Niedermeyer, J, Garin-Chesa, P, Kriz, M, Hilberg, F, Mueller, E, Bamberger, U, Rettig, WJ, Schnapp, A, Expression of the fibroblast activation protein during mouse embryo development. Int J Dev Biol 45 (2001), 445–447.
79. [79] Wang, LC, Lo, A, Scholler, J, Sun, J, Majumdar, RS, Kapoor, V, Antzis, M, Cotner, CE, Johnson, LA, Durham, AC, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res 2 (2014), 154–166.
80. [80] Brennen, WN, Rosen, DM, Chaux, A, Netto, GJ, Isaacs, JT, Denmeade, SR, Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer. Prostate 74 (2014), 1308–1319.
81. [81] Hall, DG, Boronic Acids. 2011, Wiley-VCH.
82. [82] Connolly, BA, Sanford, DG, Chiluwal, AK, Healey, SE, Peters, DE, Dimare, MT, Wu, W, Liu, Y, Maw, H, Zhou, Y, et al. Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety. J Med Chem 51 (2008), 6005–6013.