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Current Status and Biomedical Applications of Ribosome-Inactivating Proteins

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Antitumor Potential and other Emerging Medicinal Properties of Natural Compounds

Abstract

Toxin domains from plants or bacterial origin (such as Diphtheria toxin (DT) or Pseudomonas exotoxin A (PEA), which are endowed with ADP-ribosylation activity of the Eukaryotic elongation factor-2) have been extensively exploited for research and therapeutic purposes. Denileukin diftitox is the first FDA approved recombinant fusion toxin between a truncated diphtheria toxin and human interleukin-2 for the treatment of cutaneous T cell lymphomas. Ribosome-inactivating proteins (RIPs) are also a class of potent inhibitors of protein synthesis that act differently, by catalytically depurinating an adenine residue (A4324 in rat) exposed in an universally conserved stem-loop region of 23/26/28S ribosomal RNA (rRNA), also known as the “α-sarcin loop”. This causes an irreversible block in protein synthesis, leading to apoptotic cell death of mammalian target cells. RIP-containing conjugates have been used in the therapy of cancer and other incurable diseases with potential promising results and failures. In the last decade, many research efforts have been dedicated to the development of more efficient and less immunogenic chimeric fusions. In this chapter we will mainly focus on plant RIPs with the aim to report some of the most promising biomedical applications currently under investigation and further discuss their future perspectives.

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References

  1. Endo Y, Tsurugi K, Lambert JM (1988) The site of action of six different ribosome-inactivating proteins from plants on eukaryotic ribosomes: the RNA N-glycosidase activity of the proteins. Biochem Biophys Res Commun 150:1032–1036

    Article  PubMed  CAS  Google Scholar 

  2. Hartley MR, Legname G, Osborn R, Chen Z, Lord JM (1991) Single-chain ribosome inactivating proteins from plants depurinate Escherichia coli 23S ribosomal RNA. FEBS Lett 290:65–68

    Article  PubMed  CAS  Google Scholar 

  3. Stirpe F, Gasperi-Campani A, Barbieri L, Falasca A, Abbondanza A, Stevens WA (1983) Ribosome-inactivating proteins from the seeds of Saponaria officinalis L. (soapwort), of Agrostemma githago L. (corn cockle) and of Asparagus officinalis L. (asparagus), and from the latex of Hura crepitans L. (sandbox tree). Biochem J 216:617–625

    PubMed  CAS  Google Scholar 

  4. Irvin JD, Uckun FM (1992) Pokeweed antiviral protein: ribosome inactivation and therapeutic applications. Pharmacol Ther 55:279–302

    Article  PubMed  CAS  Google Scholar 

  5. Despeyroux D, Walker N, Pearce M, Fisher M, McDonnell M, Bailey SC et al (2000) Characterization of ricin heterogeneity by electrospray mass spectrometry, capillary electrophoresis, and resonant mirror. Anal Biochem 279:23–36

    Article  PubMed  CAS  Google Scholar 

  6. Chan AP, Crabtree J, Zhao Q, Lorenzi H, Orvis J, Puiu D et al (2010) Draft genome sequence of the oilseed species Ricinus communis. Nat Biotechnol 28:951–956

    Article  PubMed  CAS  Google Scholar 

  7. Barthelemy I, Martineau D, Ong M, Matsunami R, Ling N, Benatti L et al (1993) The expression of saporin, a ribosome-inactivating protein from the plant Saponaria officinalis, in Escherichia coli. J Biol Chem 268:6541–6548

    PubMed  CAS  Google Scholar 

  8. Olsnes S, Pihl A (1973) Different biological properties of the two constituent peptide chains of ricin, a toxic protein inhibiting protein synthesis. Biochemistry 12:3121–3126

    Article  PubMed  CAS  Google Scholar 

  9. Lord JM, Roberts LM, Robertus JD (1994) Ricin: structure, mode of action, and some current applications. Faseb J 8:201–208

    PubMed  CAS  Google Scholar 

  10. Peumans WJ, Hao Q, Van Damme EJ (2001) Ribosome-inactivating proteins from plants: more than RNA N-glycosidases? Faseb J 15:1493–1506

    Article  PubMed  CAS  Google Scholar 

  11. Day PJ, Lord JM, Roberts LM (1998) The deoxyribonuclease activity attributed to ribosome-inactivating proteins is due to contamination. Eur J Biochem 258:540–545

    Article  PubMed  CAS  Google Scholar 

  12. Lombardi A, Bursomanno S, Lopardo T, Traini R, Colombatti M, Ippoliti R et al (2010) Pichia pastoris as a host for secretion of toxic saporin chimeras. Faseb J 24:253–265

    Article  PubMed  CAS  Google Scholar 

  13. Sandvig K, van Deurs B (2000) Entry of ricin and Shiga toxin into cells: molecular mechanisms and medical perspectives. EMBO J 19:5943–5950

    Article  PubMed  CAS  Google Scholar 

  14. Lord JM, Deeks E, Marsden CJ, Moore K, Pateman C, Smith DC et al (2003) Retrograde transport of toxins across the endoplasmic reticulum membrane. Biochem Soc Trans 31:1260–1262

    Article  PubMed  CAS  Google Scholar 

  15. Spooner RA, Watson PD, Marsden CJ, Smith DC, Moore KA, Cook JP et al (2004) Protein disulphide-isomerase reduces ricin to its A and B chains in the endoplasmic reticulum. Biochem J 383:285–293

    Article  PubMed  CAS  Google Scholar 

  16. Madan S, Ghosh PC (1992) Interaction of gelonin with macrophages: effect of lysosomotropic amines. Exp Cell Res 198:52–58

    Article  PubMed  CAS  Google Scholar 

  17. Chan WY, Huang H, Tam SC (2003) Receptor-mediated endocytosis of trichosanthin in choriocarcinoma cells. Toxicology 186:191–203

    Article  PubMed  CAS  Google Scholar 

  18. Vago R, Marsden CJ, Lord JM, Ippoliti R, Flavell DJ, Flavell SU et al (2005) Saporin and ricin A chain follow different intracellular routes to enter the cytosol of intoxicated cells. FEBS J 272:4983–4995

    Article  PubMed  CAS  Google Scholar 

  19. Stirpe F, Barbieri L (1986) Ribosome-inactivating proteins up to date. FEBS Lett 195:1–8

    Article  PubMed  CAS  Google Scholar 

  20. Deeks ED, Cook JP, Day PJ, Smith DC, Roberts LM, Lord JM (2002) The low lysine content of ricin A chain reduces the risk of proteolytic degradation after translocation from the endoplasmic reticulum to the cytosol. Biochemistry 41:3405–3413

    Article  PubMed  CAS  Google Scholar 

  21. Fabbrini MS, Rappocciolo E, Carpani D, Solinas M, Valsasina B, Breme U et al (1997) Characterization of a saporin isoform with lower ribosome-inhibiting activity. Biochem J 322(Pt 3):719–727

    PubMed  CAS  Google Scholar 

  22. Bagga S, Seth D, Batra JK (2003) The cytotoxic activity of ribosome-inactivating protein saporin-6 is attributed to its rRNA N-glycosidase and internucleosomal DNA fragmentation activities. J Biol Chem 278:4813–4820

    Article  PubMed  CAS  Google Scholar 

  23. Zarovni N, Vago R, Solda T, Monaco L, Fabbrini MS (2007) Saporin as a novel suicide gene in anticancer gene therapy. Cancer Gene Ther 14:165–173

    Article  PubMed  CAS  Google Scholar 

  24. Marshall RS, D’Avila F, Di Cola A, Traini R, Spano L, Fabbrini MS et al (2011) Signal peptide-regulated toxicity of a plant ribosome-inactivating protein during cell stress. Plant J 65:218–229

    Article  PubMed  CAS  Google Scholar 

  25. Rajamohan F, Pugmire MJ, Kurinov IV, Uckun FM (2000) Modeling and alanine scanning mutagenesis studies of recombinant pokeweed antiviral protein. J Biol Chem 275:3382–3390

    Article  PubMed  CAS  Google Scholar 

  26. de Virgilio M, Lombardi A, Caliandro R, Fabbrini MS (2010) Ribosome-inactivating proteins: from plant defense to tumor attack. Toxins (Basel) 2:2699–2737

    Article  CAS  Google Scholar 

  27. Hartley MR, Lord JM (2004) Cytotoxic ribosome-inactivating lectins from plants. Biochim Biophys Acta 1701:1–14

    Article  PubMed  CAS  Google Scholar 

  28. Habuka N, Murakami Y, Noma M, Kudo T, Horikoshi K (1989) Amino acid sequence of Mirabilis antiviral protein, total synthesis of its gene and expression in Escherichia coli. J Biol Chem 264:6629–6637

    PubMed  CAS  Google Scholar 

  29. Chaddock JA, Lord JM, Hartley MR, Roberts LM (1994) Pokeweed antiviral protein (PAP) mutations which permit E.coli growth do not eliminate catalytic activity towards prokaryotic ribosomes. Nucleic Acids Res 22:1536–1540

    Article  PubMed  CAS  Google Scholar 

  30. Legname G, Fossati G, Monzini N, Gromo G, Marcucci F, Mascagni P et al (1995) Heterologous expression, purification, activity and conformational studies of different forms of dianthin 30. Biomed Pept Proteins Nucleic Acids 1:61–68

    PubMed  CAS  Google Scholar 

  31. Lappi DA, Ying W, Barthelemy I, Martineau D, Prieto I, Benatti L et al (1994) Expression and activities of a recombinant basic fibroblast growth factor-saporin fusion protein. J Biol Chem 269:12552–12558

    PubMed  CAS  Google Scholar 

  32. Fabbrini MS, Carpani D, Bello-Rivero I, Soria MR (1997) The amino-terminal fragment of human urokinase directs a recombinant chimeric toxin to target cells: internalization is toxin mediated. Faseb J 11:1169–1176

    PubMed  CAS  Google Scholar 

  33. Heisler I, Keller J, Tauber R, Sutherland M, Fuchs H (2003) A cleavable adapter to reduce nonspecific cytotoxicity of recombinant immunotoxins. Int J Cancer 103:277–282

    Article  PubMed  CAS  Google Scholar 

  34. Giansanti F, Di Leandro L, Koutris I, Pitari G, Fabbrini MS, Lombardi A et al (2010) Engineering a switchable toxin: the potential use of PDZ domains in the expression, targeting and activation of modified saporin variants. Protein Eng Des Sel 23:61–68

    Article  PubMed  CAS  Google Scholar 

  35. Rajamohan F, Engstrom CR, Denton TJ, Engen LA, Kourinov I, Uckun FM (1999) High-level expression and purification of biologically active recombinant pokeweed antiviral protein. Protein Expr Purif 16:359–368

    Article  PubMed  CAS  Google Scholar 

  36. Fuchs H, Bachran C, Li T, Heisler I, Durkop H, Sutherland M (2007) A cleavable molecular adapter reduces side effects and concomitantly enhances efficacy in tumor treatment by targeted toxins in mice. J Control Release 117:342–350

    Article  PubMed  CAS  Google Scholar 

  37. Fabbrini MS, Carpani D, Soria MR, Ceriotti A (2000) Cytosolic immunization allows the expression of preATF-saporin chimeric toxin in eukaryotic cells. Faseb J 14:391–398

    PubMed  CAS  Google Scholar 

  38. Cereghino JL, Cregg JM (2000) Heterologous protein expression in the methylotrophic yeast Pichia pastoris. FEMS Microbiol Rev 24:45–66

    Article  PubMed  CAS  Google Scholar 

  39. Woo JH, Liu YY, Mathias A, Stavrou S, Wang Z, Thompson J et al (2002) Gene optimization is necessary to express a bivalent anti-human anti-T cell immunotoxin in Pichia pastoris. Protein Expr Purif 25:270–282

    Article  PubMed  CAS  Google Scholar 

  40. Rajamohan F, Doumbia SO, Engstrom CR, Pendergras SL, Maher DL, Uckun FM (2000) Expression of biologically active recombinant pokeweed antiviral protein in methylotrophic yeast Pichia pastoris. Protein Expr Purif 18:193–201

    Article  PubMed  CAS  Google Scholar 

  41. Frigerio L, Vitale A, Lord JM, Ceriotti A, Roberts LM (1998) Free ricin A chain, proricin, and native toxin have different cellular fates when expressed in tobacco protoplasts. J Biol Chem 273:14194–14199

    Article  PubMed  CAS  Google Scholar 

  42. Krishnan R, McDonald KA, Dandekar AM, Jackman AP, Falk B (2002) Expression of recombinant trichosanthin, a ribosome-inactivating protein, in transgenic tobacco. J Biotechnol 97:69–88

    Article  PubMed  CAS  Google Scholar 

  43. Strebhardt K, Ullrich A (2008) Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer 8:473–480

    Article  PubMed  CAS  Google Scholar 

  44. Madhumathi J, Verma RS (2012) Therapeutic targets and recent advances in protein immunotoxins. Curr Opin Microbiol 15:300–309

    Article  PubMed  CAS  Google Scholar 

  45. Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ (2007) Immunotoxin treatment of cancer. Annu Rev Med 58:221–237

    Article  PubMed  CAS  Google Scholar 

  46. Foon KA, Todd RF 3rd (1986) Immunologic classification of leukemia and lymphoma. Blood 68:1–31

    PubMed  CAS  Google Scholar 

  47. Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB et al (2010) Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 328:240–243

    Article  PubMed  CAS  Google Scholar 

  48. Bacha P, Williams DP, Waters C, Williams JM, Murphy JR, Strom TB (1988) Interleukin 2 receptor-targeted cytotoxicity. Interleukin 2 receptor-mediated action of a diphtheria toxin-related interleukin 2 fusion protein. J Exp Med 167:612–622

    Article  PubMed  CAS  Google Scholar 

  49. Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E et al (2001) Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 19:376–388

    PubMed  CAS  Google Scholar 

  50. Kreitman RJ, Wilson WH, White JD, Stetler-Stevenson M, Jaffe ES, Giardina S et al (2000) Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol 18:1622–1636

    PubMed  CAS  Google Scholar 

  51. Blakey DC, Watson GJ, Knowles PP, Thorpe PE (1987) Effect of chemical deglycosylation of ricin A chain on the in vivo fate and cytotoxic activity of an immunotoxin composed of ricin A chain and anti-Thy 1.1 antibody. Cancer Res 47:947–952

    PubMed  CAS  Google Scholar 

  52. Schnell R, Borchmann P, Staak JO, Schindler J, Ghetie V, Vitetta ES et al (2003) Clinical evaluation of ricin A-chain immunotoxins in patients with Hodgkin’s lymphoma. Ann Oncol 14:729–736

    Article  PubMed  CAS  Google Scholar 

  53. Messmann RA, Vitetta ES, Headlee D, Senderowicz AM, Figg WD, Schindler J et al (2000) A phase I study of combination therapy with immunotoxins IgG-HD37-deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory CD19(+), CD22(+) B cell lymphoma. Clin Cancer Res 6:1302–1313

    PubMed  CAS  Google Scholar 

  54. Amlot PL, Stone MJ, Cunningham D, Fay J, Newman J, Collins R et al (1993) A phase I study of an anti-CD22-deglycosylated ricin A chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy. Blood 82:2624–2633

    PubMed  CAS  Google Scholar 

  55. Schnell R, Staak O, Borchmann P, Schwartz C, Matthey B, Hansen H et al (2002) A Phase I study with an anti-CD30 ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD30 + Hodgkin’s and non-Hodgkin’s lymphoma. Clin Cancer Res 8:1779–1786

    PubMed  CAS  Google Scholar 

  56. Uckun FM (1993) Immunotoxins for the treatment of leukaemia. Br J Haematol 85:435–438

    Article  PubMed  CAS  Google Scholar 

  57. Falini B, Bolognesi A, Flenghi L, Tazzari PL, Broe MK, Stein H et al (1992) Response of refractory Hodgkin’s disease to monoclonal anti-CD30 immunotoxin. Lancet 339:1195–1196

    Article  PubMed  CAS  Google Scholar 

  58. Pasqualucci L, Wasik M, Teicher BA, Flenghi L, Bolognesi A, Stirpe F et al (1995) Antitumor activity of anti-CD30 immunotoxin (Ber-H2/saporin) in vitro and in severe combined immunodeficiency disease mice xenografted with human CD30 + anaplastic large-cell lymphoma. Blood 85:2139–2146

    PubMed  CAS  Google Scholar 

  59. Terenzi A, Bolognesi A, Pasqualucci L, Flenghi L, Pileri S, Stein H et al (1996) Anti-CD30 (BER = H2) immunotoxins containing the type-1 ribosome-inactivating proteins momordin and PAP-S (pokeweed antiviral protein from seeds) display powerful antitumour activity against CD30 + tumour cells in vitro and in SCID mice. Br J Haematol 92:872–879

    Article  PubMed  CAS  Google Scholar 

  60. Bolognesi A, Tazzari PL, Olivieri F, Polito L, Lemoli R, Terenzi A et al (1998) Evaluation of immunotoxins containing single-chain ribosome-inactivating proteins and an anti-CD22 monoclonal antibody (OM124): in vitro and in vivo studies. Br J Haematol 101:179–188

    Article  PubMed  CAS  Google Scholar 

  61. Flavell DJ, Noss A, Pulford KA, Ling N, Flavell SU (1997) Systemic therapy with 3BIT, a triple combination cocktail of anti-CD19, -CD22, and -CD38-saporin immunotoxins, is curative of human B-cell lymphoma in severe combined immunodeficient mice. Cancer Res 57:4824–4829

    PubMed  CAS  Google Scholar 

  62. Polito L, Bortolotti M, Farini V, Pedrazzi M, Tazzari PL, Bolognesi A (2009) ATG-saporin-S6 immunotoxin: a new potent and selective drug to eliminate activated lymphocytes and lymphoma cells. Br J Haematol 147:710–718

    Article  PubMed  CAS  Google Scholar 

  63. Polito L, Bortolotti M, Pedrazzi M, Bolognesi A (2011) Immunotoxins and other conjugates containing saporin-s6 for cancer therapy. Toxins (Basel) 3:697–720

    Article  CAS  Google Scholar 

  64. Parameswaran R, Yu M, Lyu MA, Lim M, Rosenblum MG, Groffen J et al (2012) Treatment of acute lymphoblastic leukemia with an rGel/BLyS fusion toxin. Leukemia 26:1786–1796

    Article  PubMed  CAS  Google Scholar 

  65. ten Cate B, de Bruyn M, Wei Y, Bremer E, Helfrich W (2010) Targeted elimination of leukemia stem cells; a new therapeutic approach in hemato-oncology. Curr Drug Targets 11:95–110

    Article  PubMed  Google Scholar 

  66. Appelbaum FR (1997) Allogeneic hematopoietic stem cell transplantation for acute leukemia. Semin Oncol 24:114–123

    PubMed  CAS  Google Scholar 

  67. Bregni M, Siena S, Subar M, Villa S, Bonadonna G, Dalla-Favera R et al (1989) Detection of occult leukemic cells in the autologous bone marrow graft of a patient with T-cell acute lymphoblastic leukemia by a highly specific and sensitive assay. Haematologica 74:11–14

    PubMed  CAS  Google Scholar 

  68. Lemoli RM, Tazzari PL, Fortuna A, Bolognesi A, Gulati SC, Stirpe F et al (1994) Positive selection of hematopoietic CD34 + stem cells provides ‘indirect purging’ of CD34- lymphoid cells and the purging efficiency is increased by anti-CD2 and anti-CD30 immunotoxins. Bone Marrow Transpl 13:465–471

    CAS  Google Scholar 

  69. Dinota A, Barbieri L, Gobbi M, Tazzari PL, Rizzi S, Bontadini A et al (1989) An immunotoxin containing momordin suitable for bone marrow purging in multiple myeloma patients. Br J Cancer 60:315–319

    Article  PubMed  CAS  Google Scholar 

  70. McGraw KJ, Rosenblum MG, Cheung L, Scheinberg DA (1994) Characterization of murine and humanized anti-CD33, gelonin immunotoxins reactive against myeloid leukemias. Cancer Immunol Immunother 39:367–374

    Article  PubMed  CAS  Google Scholar 

  71. LaCasse EC, Saleh MT, Patterson B, Minden MD, Gariepy J (1996) Shiga-like toxin purges human lymphoma from bone marrow of severe combined immunodeficient mice. Blood 88:1561–1567

    PubMed  CAS  Google Scholar 

  72. Kelly DA (2005) Long-term challenges of immunosuppression in pediatric patients. Transpl Proc 37:1657–1662

    Article  CAS  Google Scholar 

  73. Fishman JA, Rubin RH (1998) Infection in organ-transplant recipients. N Engl J Med 338:1741–1751

    Article  PubMed  CAS  Google Scholar 

  74. Rennie DP, McGregor AM, Wright J, Weetman AP, Hall R, Thorpe P (1983) An immunotoxin of ricin A chain conjugated to thyroglobulin selectively suppresses the antithyroglobulin autoantibody response. Lancet 2:1338–1340

    Article  PubMed  CAS  Google Scholar 

  75. Hess PR, Barnes C, Woolard MD, Johnson MD, Cullen JM, Collins EJ et al (2007) Selective deletion of antigen-specific CD8 + T cells by MHC class I tetramers coupled to the type I ribosome-inactivating protein saporin. Blood 109:3300–3307

    Article  PubMed  CAS  Google Scholar 

  76. Hossann M, Li Z, Shi Y, Kreilinger U, Buttner J, Vogel PD et al (2006) Novel immunotoxin: a fusion protein consisting of gelonin and an acetylcholine receptor fragment as a potential immunotherapeutic agent for the treatment of Myasthenia gravis. Protein Expr Purif 46:73–84

    Article  PubMed  CAS  Google Scholar 

  77. van Roon JA, van Vuuren AJ, Wijngaarden S, Jacobs KM, Bijlsma JW, Lafeber FP et al (2003) Selective elimination of synovial inflammatory macrophages in rheumatoid arthritis by an Fcgamma receptor I-directed immunotoxin. Arthritis Rheum 48:1229–1238

    Article  PubMed  CAS  Google Scholar 

  78. Nagai T, Tanaka M, Tsuneyoshi Y, Matsushita K, Sunahara N, Matsuda T et al (2006) In vitro and in vivo efficacy of a recombinant immunotoxin against folate receptor beta on the activation and proliferation of rheumatoid arthritis synovial cells. Arthritis Rheum 54:3126–3134

    Article  PubMed  CAS  Google Scholar 

  79. Stepanov AV, Belogurov AA Jr, Ponomarenko NA, Stremovskiy OA, Kozlov LV, Bichucher AM et al (2011) Design of targeted B cell killing agents. PLoS ONE 6:e20991

    Article  PubMed  CAS  Google Scholar 

  80. Chandler LA, Sosnowski BA, McDonald JR, Price JE, Aukerman SL, Baird A et al (1998) Targeting tumor cells via EGF receptors: selective toxicity of an HBEGF-toxin fusion protein. Int J Cancer 78:106–111

    Article  PubMed  CAS  Google Scholar 

  81. Hoffmann C, Bachran C, Stanke J, Elezkurtaj S, Kaufmann AM, Fuchs H et al (2010) Creation and characterization of a xenograft model for human cervical cancer. Gynecol Oncol 118:76–80

    Article  PubMed  Google Scholar 

  82. Bachran D, Schneider S, Bachran C, Urban R, Weng A, Melzig MF et al (2010) Epidermal growth factor receptor expression affects the efficacy of the combined application of saponin and a targeted toxin on human cervical carcinoma cells. Int J Cancer 127:1453–1461

    Article  PubMed  CAS  Google Scholar 

  83. Zhou X, Qiu J, Wang Z, Huang N, Li X, Li Q et al (2012) In vitro and in vivo anti-tumor activities of anti-EGFR single-chain variable fragment fused with recombinant gelonin toxin. J Cancer Res Clin Oncol 138:1081–1090

    Article  PubMed  CAS  Google Scholar 

  84. Beitz JG, Davol P, Clark JW, Kato J, Medina M, Frackelton AR Jr et al (1992) Antitumor activity of basic fibroblast growth factor-saporin mitotoxin in vitro and in vivo. Cancer Res 52:227–230

    PubMed  CAS  Google Scholar 

  85. Ying W, Martineau D, Beitz J, Lappi DA, Baird A (1994) Anti-B16-F10 melanoma activity of a basic fibroblast growth factor-saporin mitotoxin. Cancer 74:848–853

    Article  PubMed  CAS  Google Scholar 

  86. Davol P, Frackelton AR Jr (1996) The mitotoxin, basic fibroblast growth factor-saporin, effectively targets human prostatic carcinoma in an animal model. J Urol 156:1174–1179

    Article  PubMed  CAS  Google Scholar 

  87. Kuroda K, Liu H, Kim S, Guo M, Navarro V, Bander NH (2010) Saporin toxin-conjugated monoclonal antibody targeting prostate-specific membrane antigen has potent anticancer activity. Prostate 70:1286–1294

    PubMed  CAS  Google Scholar 

  88. Siva AC, Wild MA, Kirkland RE, Nolan MJ, Lin B, Maruyama T et al (2008) Targeting CUB domain-containing protein 1 with a monoclonal antibody inhibits metastasis in a prostate cancer model. Cancer Res 68:3759–3766

    Article  PubMed  CAS  Google Scholar 

  89. Duxbury MS, Ito H, Ashley SW, Whang EE (2004) CEACAM6 as a novel target for indirect type 1 immunotoxin-based therapy in pancreatic adenocarcinoma. Biochem Biophys Res Commun 317:837–843

    Article  PubMed  CAS  Google Scholar 

  90. Foehr ED, Lorente G, Kuo J, Ram R, Nikolich K, Urfer R (2006) Targeting of the receptor protein tyrosine phosphatase beta with a monoclonal antibody delays tumor growth in a glioblastoma model. Cancer Res 66:2271–2278

    Article  PubMed  CAS  Google Scholar 

  91. Bruland OS, Fodstad O, Stenwig AE, Pihl A (1988) Expression and characteristics of a novel human osteosarcoma-associated cell surface antigen. Cancer Res 48:5302–5309

    PubMed  CAS  Google Scholar 

  92. Anderson PM, Meyers DE, Hasz DE, Covalcuic K, Saltzman D, Khanna C et al (1995) In vitro and in vivo cytotoxicity of an anti-osteosarcoma immunotoxin containing pokeweed antiviral protein. Cancer Res 55:1321–1327

    PubMed  CAS  Google Scholar 

  93. Zhou H, Marks JW, Hittelman WN, Yagita H, Cheung LH, Rosenblum MG et al (2011) Development and characterization of a potent immunoconjugate targeting the Fn14 receptor on solid tumor cells. Mol Cancer Ther 10:1276–1288

    Article  PubMed  CAS  Google Scholar 

  94. Momburg F, Moldenhauer G, Hammerling GJ, Moller P (1987) Immunohistochemical study of the expression of a Mr 34,000 human epithelium-specific surface glycoprotein in normal and malignant tissues. Cancer Res 47:2883–2891

    PubMed  CAS  Google Scholar 

  95. Cizeau J, Grenkow DM, Brown JG, Entwistle J, MacDonald GC (2009) Engineering and biological characterization of VB6-845, an anti-EpCAM immunotoxin containing a T-cell epitope-depleted variant of the plant toxin bouganin. J Immunother 32:574–584

    Article  PubMed  CAS  Google Scholar 

  96. Kreitman RJ (2009) Recombinant immunotoxins containing truncated bacterial toxins for the treatment of hematologic malignancies. BioDrugs 23:1–13

    Article  PubMed  CAS  Google Scholar 

  97. Selbo PK, Weyergang A, Hogset A, Norum OJ, Berstad MB, Vikdal M et al (2010) Photochemical internalization provides time- and space-controlled endolysosomal escape of therapeutic molecules. J Control Release 148:2–12

    Article  PubMed  CAS  Google Scholar 

  98. Jankun J, Hart R (1997) Method of delivery of a medicament to a cancer cell using a pathway of plasminogen activator material. US Patent 5,679,350, 21 Oct 1997

    Google Scholar 

  99. Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE (1997) Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 3:1222–1227

    Article  PubMed  CAS  Google Scholar 

  100. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307

    Article  PubMed  CAS  Google Scholar 

  101. Burrows FJ, Thorpe PE (1993) Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature. Proc Natl Acad Sci U S A 90:8996–9000

    Article  PubMed  CAS  Google Scholar 

  102. Burrows FJ, Derbyshire EJ, Tazzari PL, Amlot P, Gazdar AF, King SW et al (1995) Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin Cancer Res 1:1623–1634

    PubMed  CAS  Google Scholar 

  103. Griffioen AW, Coenen MJ, Damen CA, Hellwig SM, van Weering DH, Vooys W et al (1997) CD44 is involved in tumor angiogenesis; an activation antigen on human endothelial cells. Blood 90:1150–1159

    PubMed  CAS  Google Scholar 

  104. Bussolati B, Grange C, Bruno S, Buttiglieri S, Deregibus MC, Tei L et al (2006) Neural-cell adhesion molecule (NCAM) expression by immature and tumor-derived endothelial cells favors cell organization into capillary-like structures. Exp Cell Res 312:913–924

    Article  PubMed  CAS  Google Scholar 

  105. Veenendaal LM, Jin H, Ran S, Cheung L, Navone N, Marks JW et al (2002) In vitro and in vivo studies of a VEGF121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors. Proc Natl Acad Sci U S A 99:7866–7871

    Article  PubMed  CAS  Google Scholar 

  106. Ran S, Mohamedali KA, Luster TA, Thorpe PE, Rosenblum MG (2005) The vascular-ablative agent VEGF(121)/rGel inhibits pulmonary metastases of MDA-MB-231 breast tumors. Neoplasia 7:486–496

    Article  PubMed  CAS  Google Scholar 

  107. Matsuno F, Haruta Y, Kondo M, Tsai H, Barcos M, Seon BK (1999) Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies. Clin Cancer Res 5:371–382

    PubMed  CAS  Google Scholar 

  108. Tsunoda S, Ohizumi I, Matsui J, Koizumi K, Wakai Y, Makimoto H et al (1999) Specific binding of TES-23 antibody to tumour vascular endothelium in mice, rats and human cancer tissue: a novel drug carrier for cancer targeting therapy. Br J Cancer 81:1155–1161

    Article  PubMed  CAS  Google Scholar 

  109. Bussolati B, Grange C, Tei L, Deregibus MC, Ercolani M, Aime S et al (2007) Targeting of human renal tumor-derived endothelial cells with peptides obtained by phage display. J Mol Med (Berl) 85:897–906

    Article  CAS  Google Scholar 

  110. Thorpe PE (2004) Vascular targeting agents as cancer therapeutics. Clin Cancer Res 10:415–427

    Article  PubMed  Google Scholar 

  111. Kim S, Mohamedali KA, Cheung LH, Rosenblum MG (2007) Overexpression of biologically active VEGF121 fusion proteins in Escherichia coli. J Biotechnol 128:638–647

    Article  PubMed  CAS  Google Scholar 

  112. Mohamedali KA, Ran S, Gomez-Manzano C, Ramdas L, Xu J, Kim S et al (2011) Cytotoxicity of VEGF(121)/rGel on vascular endothelial cells resulting in inhibition of angiogenesis is mediated via VEGFR-2. BMC Cancer 11:358

    Article  PubMed  CAS  Google Scholar 

  113. Akiyama H, Mohamedali KA, E Silva RL, Kachi S, Shen J, Hatara C et al (2005) Vascular targeting of ocular neovascularization with a vascular endothelial growth factor121/gelonin chimeric protein. Mol Pharmacol 68:1543–1550

    Google Scholar 

  114. Cho EJ, Yang J, Mohamedali KA, Lim EK, Kim EJ, Farhangfar CJ et al (2011) Sensitive angiogenesis imaging of orthotopic bladder tumors in mice using a selective magnetic resonance imaging contrast agent containing VEGF121/rGel. Invest Radiol 46:441–449

    Article  PubMed  Google Scholar 

  115. Shan L (2011) Vascular endothelial growth factor A isoform 121-gelonin fusion protein-conjugated manganese ferrite nanoparticles. Molecular Imaging and Contrast Agent Database (MICAD)

    Google Scholar 

  116. Arap W, Pasqualini R, Ruoslahti E (1998) Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279:377–380

    Article  PubMed  CAS  Google Scholar 

  117. Corti A, Curnis F (2011) Tumor vasculature targeting through NGR peptide-based drug delivery systems. Curr Pharm Biotechnol 12:1128–1134

    Article  PubMed  CAS  Google Scholar 

  118. Zarovni N, Monaco L, Corti A (2004) Inhibition of tumor growth by intramuscular injection of cDNA encoding tumor necrosis factor alpha coupled to NGR and RGD tumor-homing peptides. Hum Gene Ther 15:373–382

    Article  PubMed  CAS  Google Scholar 

  119. Wiley RG, Blessing WW, Reis DJ (1982) Suicide transport: destruction of neurons by retrograde transport of ricin, abrin, and modeccin. Science 216:889–890

    Article  PubMed  CAS  Google Scholar 

  120. Wiley RG, Stirpe F (1987) Neuronotoxicity of axonally transported toxic lectins, abrin, modeccin and volkensin in rat peripheral nervous system. Neuropathol Appl Neurobiol 13:39–53

    Article  PubMed  CAS  Google Scholar 

  121. Rossner S, Schliebs R, Hartig W, Bigl V (1995) 192IGG-saporin-induced selective lesion of cholinergic basal forebrain system: neurochemical effects on cholinergic neurotransmission in rat cerebral cortex and hippocampus. Brain Res Bull 38:371–381

    Article  PubMed  CAS  Google Scholar 

  122. Quinlivan M, Chalon S, Vergote J, Henderson J, Katsifis A, Kassiou M et al (2007) Decreased vesicular acetylcholine transporter and alpha(4)beta(2) nicotinic receptor density in the rat brain following 192 IgG-saporin immunolesioning. Neurosci Lett 415:97–101

    Article  PubMed  CAS  Google Scholar 

  123. Fine A, Hoyle C, Maclean CJ, Levatte TL, Baker HF, Ridley RM (1997) Learning impairments following injection of a selective cholinergic immunotoxin, ME20.4 IgG-saporin, into the basal nucleus of Meynert in monkeys. Neuroscience 81:331–343

    Article  PubMed  CAS  Google Scholar 

  124. Kuczewski N, Aztiria E, Leanza G, Domenici L (2005) Selective cholinergic immunolesioning affects synaptic plasticity in developing visual cortex. Eur J Neurosci 21:1807–1814

    Article  PubMed  CAS  Google Scholar 

  125. Ramanathan D, Tuszynski MH, Conner JM (2009) The basal forebrain cholinergic system is required specifically for behaviorally mediated cortical map plasticity. J Neurosci 29:5992–6000

    Article  PubMed  CAS  Google Scholar 

  126. Kamke MR, Brown M, Irvine DR (2005) Origin and immunolesioning of cholinergic basal forebrain innervation of cat primary auditory cortex. Hear Res 206:89–106

    Article  PubMed  CAS  Google Scholar 

  127. Ballmaier M, Casamenti F, Scali C, Mazzoncini R, Zoli M, Pepeu G et al (2002) Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis. Neuroscience 114:91–98

    Article  PubMed  CAS  Google Scholar 

  128. Picklo MJ, Wiley RG, Lappi DA, Robertson D (1994) Noradrenergic lesioning with an anti-dopamine beta-hydroxylase immunotoxin. Brain Res 666:195–200

    Article  PubMed  CAS  Google Scholar 

  129. Wiley RG, Harrison MB, Levey AI, Lappi DA (2003) Destruction of midbrain dopaminergic neurons by using immunotoxin to dopamine transporter. Cell Mol Neurobiol 23:839–850

    Article  PubMed  CAS  Google Scholar 

  130. Kwok KH, Law KB, Wong RN, Yung KK (2000) Immunolesioning of glutamate receptor GluR1-containing neurons in the rat neostriatum using a novel immunotoxin. Cell Mol Neurobiol 20:483–496

    Article  PubMed  CAS  Google Scholar 

  131. Monti B, D’Alessandro C, Farini V, Bolognesi A, Polazzi E, Contestabile A et al (2007) In vitro and in vivo toxicity of type 2 ribosome-inactivating proteins lanceolin and stenodactylin on glial and neuronal cells. Neurotoxicology 28:637–644

    Article  PubMed  CAS  Google Scholar 

  132. Mantyh PW, Allen CJ, Ghilardi JR, Rogers SD, Mantyh CR, Liu H et al (1995) Rapid endocytosis of a G protein-coupled receptor: substance P evoked internalization of its receptor in the rat striatum in vivo. Proc Natl Acad Sci U S A 92:2622–2626

    Article  PubMed  CAS  Google Scholar 

  133. Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM et al (1999) Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 286:1558–1561

    Article  PubMed  CAS  Google Scholar 

  134. Allen JW, Mantyh PW, Horais K, Tozier N, Rogers SD, Ghilardi JR et al (2006) Safety evaluation of intrathecal substance P-saporin, a targeted neurotoxin, in dogs. Toxicol Sci 91:286–298

    Article  PubMed  CAS  Google Scholar 

  135. Holmes MA, Foote J (1997) Structural consequences of humanizing an antibody. J Immunol 158:2192–2201

    PubMed  CAS  Google Scholar 

  136. Presta LG (2006) Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev 58:640–656

    Article  PubMed  CAS  Google Scholar 

  137. Sharkey RM, Goldenberg DM (2008) Use of antibodies and immunoconjugates for the therapy of more accessible cancers. Adv Drug Deliv Rev 60:1407–1420

    Article  PubMed  CAS  Google Scholar 

  138. Hwang WY, Foote J (2005) Immunogenicity of engineered antibodies. Methods 36:3–10

    Article  PubMed  CAS  Google Scholar 

  139. Winter G, Griffiths AD, Hawkins RE, Hoogenboom HR (1994) Making antibodies by phage display technology. Annu Rev Immunol 12:433–455

    Article  PubMed  CAS  Google Scholar 

  140. Bruggemann M, Spicer C, Buluwela L, Rosewell I, Barton S, Surani MA et al (1991) Human antibody production in transgenic mice: expression from 100 kb of the human IgH locus. Eur J Immunol 21:1323–1326

    Article  PubMed  CAS  Google Scholar 

  141. Borthakur G, Rosenblum M, Talpaz M, Daver N, Ravandi F, Faderl S et al (2012) Phase 1 study of anti-CD33 immunotoxin HUM-195/rGEL in patients withadvanced myeloid malignancies. Haematologica

    Google Scholar 

  142. Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC et al (2007) Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res 13:5144–5149

    Article  PubMed  CAS  Google Scholar 

  143. Wayne AS, Kreitman RJ, Findley HW, Lew G, Delbrook C, Steinberg SM et al (2010) Anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-positive hematologic malignancies of childhood: preclinical studies and phase I clinical trial. Clin Cancer Res 16:1894–1903

    Article  PubMed  CAS  Google Scholar 

  144. Dinndorf P, Krailo M, Liu-Mares W, Frierdich S, Sondel P, Reaman G (2001) Phase I trial of anti-B4-blocked ricin in pediatric patients with leukemia and lymphoma. J Immunother 24:511–516

    Article  PubMed  CAS  Google Scholar 

  145. Molineux G (2003) Pegylation: engineering improved biopharmaceuticals for oncology. Pharmacotherapy 23:3S–8S

    Article  PubMed  CAS  Google Scholar 

  146. Arpicco S, Dosio F, Bolognesi A, Lubelli C, Brusa P, Stella B et al (2002) Novel poly(ethylene glycol) derivatives for preparation of ribosome-inactivating protein conjugates. Bioconjug Chem 13:757–765

    Article  PubMed  CAS  Google Scholar 

  147. An Q, Lei Y, Jia N, Zhang X, Bai Y, Yi J et al (2007) Effect of site-directed PEGylation of trichosanthin on its biological activity, immunogenicity, and pharmacokinetics. Biomol Eng 24:643–649

    Article  PubMed  CAS  Google Scholar 

  148. Meng Y, Liu S, Li J, Meng Y, Zhao X (2012) Preparation of an antitumor and antivirus agent: chemical modification of alpha-MMC and MAP30 from Momordica Charantia L. with covalent conjugation of polyethyelene glycol. Int J Nanomedicine 7:3133–3142

    PubMed  Google Scholar 

  149. Hu RG, Zhai QW, He WJ, Mei L, Liu WY (2002) Bioactivities of ricin retained and its immunoreactivity to anti-ricin polyclonal antibodies alleviated through pegylation. Int J Biochem Cell Biol 34:396–402

    Article  PubMed  CAS  Google Scholar 

  150. Chan WL, Shaw PC, Li XB, Xu QF, He XH, Tam SC (1999) Lowering of trichosanthin immunogenicity by site-specific coupling to dextran. Biochem Pharmacol 57:927–934

    Article  PubMed  CAS  Google Scholar 

  151. Onda M, Nagata S, FitzGerald DJ, Beers R, Fisher RJ, Vincent JJ et al (2006) Characterization of the B cell epitopes associated with a truncated form of Pseudomonas exotoxin (PE38) used to make immunotoxins for the treatment of cancer patients. J Immunol 177:8822–8834

    PubMed  CAS  Google Scholar 

  152. Onda M, Beers R, Xiang L, Nagata S, Wang QC, Pastan I (2008) An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes. Proc Natl Acad Sci U S A 105:11311–11316

    Article  PubMed  CAS  Google Scholar 

  153. Vallera DA, Oh S, Chen H, Shu Y, Frankel AE (2010) Bioengineering a unique deimmunized bispecific targeted toxin that simultaneously recognizes human CD22 and CD19 receptors in a mouse model of B-cell metastases. Mol Cancer Ther 9:1872–1883

    Article  PubMed  CAS  Google Scholar 

  154. Liu W, Onda M, Kim C, Xiang L, Weldon JE, Lee B et al (2012) A recombinant immunotoxin engineered for increased stability by adding a disulfide bond has decreased immunogenicity. Protein Eng Des Sel 25:1–6

    Article  PubMed  CAS  Google Scholar 

  155. Olson MA, Carra JH, Roxas-Duncan V, Wannemacher RW, Smith LA, Millard CB (2004) Finding a new vaccine in the ricin protein fold. Protein Eng Des Sel 17:391–397

    Article  PubMed  CAS  Google Scholar 

  156. Baluna R, Rizo J, Gordon BE, Ghetie V, Vitetta ES (1999) Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome. Proc Natl Acad Sci U S A 96:3957–3962

    Article  PubMed  CAS  Google Scholar 

  157. Baluna R, Coleman E, Jones C, Ghetie V, Vitetta ES (2000) The effect of a monoclonal antibody coupled to ricin A chain-derived peptides on endothelial cells in vitro: insights into toxin-mediated vascular damage. Exp Cell Res 258:417–424

    Article  PubMed  CAS  Google Scholar 

  158. Vitetta ES (2000) Immunotoxins and vascular leak syndrome. Cancer J 6(Suppl 3):S218–S224

    PubMed  Google Scholar 

  159. Coulson BS, Londrigan SL, Lee DJ (1997) Rotavirus contains integrin ligand sequences and a disintegrin-like domain that are implicated in virus entry into cells. Proc Natl Acad Sci U S A 94:5389–5394

    Article  PubMed  CAS  Google Scholar 

  160. Smallshaw JE, Ghetie V, Rizo J, Fulmer JR, Trahan LL, Ghetie MA et al (2003) Genetic engineering of an immunotoxin to eliminate pulmonary vascular leak in mice. Nat Biotechnol 21:387–391

    Article  PubMed  CAS  Google Scholar 

  161. Bonini F, Traini R, Comper F, Fracasso G, Tomazzolli R, Dalla Serra M et al (2006) N-terminal deletion affects catalytic activity of saporin toxin. J Cell Biochem 98:1130–1139

    Google Scholar 

  162. Chan SH, Shaw PC, Mulot SF, Xu LH, Chan WL, Tam SC et al (2000) Engineering of a mini-trichosanthin that has lower antigenicity by deleting its C-terminal amino acid residues. Biochem Biophys Res Commun 270:279–285

    Article  PubMed  CAS  Google Scholar 

  163. An Q, Wei S, Mu S, Zhang X, Lei Y, Zhang W et al (2006) Mapping the antigenic determinants and reducing the immunogenicity of trichosanthin by site-directed mutagenesis. J Biomed Sci 13:637–643

    Article  PubMed  CAS  Google Scholar 

  164. Entwistle J, Brown JG, Chooniedass S, Cizeau J, Macdonald GC (2012) Preclinical evaluation of VB6-845: an anti-EpCAM immunotoxin with reduced immunogenic potential. Cancer Biother Radiopharm

    Google Scholar 

  165. MacDonald GC, Rasamoelisolo M, Entwistle J, Cizeau J, Bosc D, Cuthbert W et al (2009) A phase I clinical study of VB4-845: weekly intratumoral administration of an anti-EpCAM recombinant fusion protein in patients with squamous cell carcinoma of the head and neck. Drug Des Devel Ther 2:105–114

    PubMed  Google Scholar 

  166. MacDonald GC, Rasamoelisolo M, Entwistle J, Cuthbert W, Kowalski M, Spearman MA et al (2009) A phase I clinical study of intratumorally administered VB4-845, an anti-epithelial cell adhesion molecule recombinant fusion protein, in patients with squamous cell carcinoma of the head and neck. Med Oncol 26:257–264

    Article  PubMed  CAS  Google Scholar 

  167. Zarovni N, Vago R, Fabbrini MS (2009) Saporin suicide gene therapy. Methods Mol Biol 542:261–283

    Article  PubMed  CAS  Google Scholar 

  168. Martin V, Cortes ML, de Felipe P, Farsetti A, Calcaterra NB, Izquierdo M (2000) Cancer gene therapy by thyroid hormone-mediated expression of toxin genes. Cancer Res 60:3218–3224

    PubMed  CAS  Google Scholar 

  169. Gommans WM, van Eert SJ, McLaughlin PM, Harmsen MC, Yamamoto M, Curiel DT et al (2006) The carcinoma-specific epithelial glycoprotein-2 promoter controls efficient and selective gene expression in an adenoviral context. Cancer Gene Ther 13:150–158

    Article  PubMed  CAS  Google Scholar 

  170. Lipinski KS, Djeha HA, Gawn J, Cliffe S, Maitland NJ, Palmer DH et al (2004) Optimization of a synthetic beta-catenin-dependent promoter for tumor-specific cancer gene therapy. Mol Ther 10:150–161

    Article  PubMed  CAS  Google Scholar 

  171. Li Y, McCadden J, Ferrer F, Kruszewski M, Carducci M, Simons J et al (2002) Prostate-specific expression of the diphtheria toxin A chain (DT-A): studies of inducibility and specificity of expression of prostate-specific antigen promoter-driven DT-A adenoviral-mediated gene transfer. Cancer Res 62:2576–2582

    PubMed  CAS  Google Scholar 

  172. Zabala M, Wang L, Hernandez-Alcoceba R, Hillen W, Qian C, Prieto J et al (2004) Optimization of the Tet-on system to regulate interleukin 12 expression in the liver for the treatment of hepatic tumors. Cancer Res 64:2799–2804

    Article  PubMed  CAS  Google Scholar 

  173. Schmidt M, Gruensfelder P, Roller J, Hagen R (2011) Suicide gene therapy in head and neck carcinoma cells: an in vitro study. Int J Mol Med 27:591–597

    Article  PubMed  CAS  Google Scholar 

  174. Beltinger C, Uckert W, Debatin KM (2001) Suicide gene therapy for pediatric tumors. J Mol Med (Berl) 78:598–612

    Article  CAS  Google Scholar 

  175. Boeckle S, Wagner E (2006) Optimizing targeted gene delivery: chemical modification of viral vectors and synthesis of artificial virus vector systems. Aaps J 8:E731–E742

    Article  PubMed  CAS  Google Scholar 

  176. Bourbeau D, Lau CJ, Jaime J, Koty Z, Zehntner SP, Lavoie G et al (2007) Improvement of antitumor activity by gene amplification with a replicating but nondisseminating adenovirus. Cancer Res 67:3387–3395

    Article  PubMed  CAS  Google Scholar 

  177. Ye X, Liang M, Meng X, Ren X, Chen H, Li ZY et al (2003) Insulation from viral transcriptional regulatory elements enables improvement to hepatoma-specific gene expression from adenovirus vectors. Biochem Biophys Res Commun 307:759–764

    Article  PubMed  CAS  Google Scholar 

  178. Bergen JM, Park IK, Horner PJ, Pun SH (2008) Nonviral approaches for neuronal delivery of nucleic acids. Pharm Res 25:983–998

    Article  PubMed  CAS  Google Scholar 

  179. Al-Dosari MS, Gao X (2009) Nonviral gene delivery: principle, limitations, and recent progress. Aaps J 11:671–681

    Article  PubMed  CAS  Google Scholar 

  180. Glinka EM (2012) Eukaryotic expression vectors bearing genes encoding cytotoxic proteins for cancer gene therapy. Plasmid 68:69–85

    Article  PubMed  CAS  Google Scholar 

  181. Patil SD, Rhodes DG, Burgess DJ (2005) DNA-based therapeutics and DNA delivery systems: a comprehensive review. Aaps J 7:E61–E77

    Article  PubMed  CAS  Google Scholar 

  182. Duarte S, Carle G, Faneca H, Lima MC, Pierrefite-Carle V (2012) Suicide gene therapy in cancer: where do we stand now? Cancer Lett 324:160–170

    Article  PubMed  CAS  Google Scholar 

  183. Hoganson DK, Chandler LA, Fleurbaaij GA, Ying W, Black ME, Doukas J et al (1998) Targeted delivery of DNA encoding cytotoxic proteins through high-affinity fibroblast growth factor receptors. Hum Gene Ther 9:2565–2575

    Article  PubMed  CAS  Google Scholar 

  184. Seow Y, Wood MJ (2009) Biological gene delivery vehicles: beyond viral vectors. Mol Ther 17:767–777

    Article  PubMed  CAS  Google Scholar 

  185. Wei MQ, Ellem KA, Dunn P, West MJ, Bai CX, Vogelstein B (2007) Facultative or obligate anaerobic bacteria have the potential for multimodality therapy of solid tumours. Eur J Cancer 43:490–496

    Article  PubMed  Google Scholar 

  186. Akin D, Sturgis J, Ragheb K, Sherman D, Burkholder K, Robinson JP et al (2007) Bacteria-mediated delivery of nanoparticles and cargo into cells. Nat Nanotechnol 2:441–449

    Article  PubMed  CAS  Google Scholar 

  187. Nemunaitis J, Cunningham C, Senzer N, Kuhn J, Cramm J, Litz C et al (2003) Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther 10:737–744

    Article  PubMed  CAS  Google Scholar 

  188. Toso JF, Gill VJ, Hwu P, Marincola FM, Restifo NP, Schwartzentruber DJ et al (2002) Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol 20:142–152

    Article  PubMed  Google Scholar 

  189. King I, Bermudes D, Lin S, Belcourt M, Pike J, Troy K et al (2002) Tumor-targeted Salmonella expressing cytosine deaminase as an anticancer agent. Hum Gene Ther 13:1225–1233

    Article  PubMed  CAS  Google Scholar 

  190. Friedlos F, Lehouritis P, Ogilvie L, Hedley D, Davies L, Bermudes D et al (2008) Attenuated Salmonella targets prodrug activating enzyme carboxypeptidase G2 to mouse melanoma and human breast and colon carcinomas for effective suicide gene therapy. Clin Cancer Res 14:4259–4266

    Article  PubMed  CAS  Google Scholar 

  191. Cheng CM, Lu YL, Chuang KH, Hung WC, Shiea J, Su YC et al (2008) Tumor-targeting prodrug-activating bacteria for cancer therapy. Cancer Gene Ther 15:393–401

    Article  PubMed  CAS  Google Scholar 

  192. Jabr-Milane L, van Vlerken L, Devalapally H, Shenoy D, Komareddy S, Bhavsar M et al (2008) Multi-functional nanocarriers for targeted delivery of drugs and genes. J Control Release 130:121–128

    Article  PubMed  CAS  Google Scholar 

  193. Iyer AK, Khaled G, Fang J, Maeda H (2006) Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today 11:812–818

    Article  PubMed  CAS  Google Scholar 

  194. Yip WL, Weyergang A, Berg K, Tonnesen HH, Selbo PK (2007) Targeted delivery and enhanced cytotoxicity of cetuximab-saporin by photochemical internalization in EGFR-positive cancer cells. Mol Pharm 4:241–251

    Article  PubMed  CAS  Google Scholar 

  195. Fuchs H, Bachran D, Panjideh H, Schellmann N, Weng A, Melzig MF et al (2009) Saponins as tool for improved targeted tumor therapies. Curr Drug Targets 10:140–151

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Dibit-HSR Scientific Institute and Università Vita-Salute San Raffaele, via Olgettina 58, 20132, Milan, Italy

    Riccardo Vago

  2. Department of Life, Health and Environmental Sciences, University of L’Aquila, Via Vetoio snc. Coppito, 67010, L’Aquila, Italy

    Rodolfo Ippoliti

  3. Istituto Nazionale di Genetica Molecolare (INGM), Via Francesco Sforza 28, 20122, Milan, Italy

    Maria Serena Fabbrini

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  1. , Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Bayview Boulevard Street 251, Baltimore, 21224-6825, Maryland, USA

    Evandro Fei Fang

  2. , School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong SAR

    Tzi Bun Ng

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Vago, R., Ippoliti, R., Fabbrini, M.S. (2013). Current Status and Biomedical Applications of Ribosome-Inactivating Proteins. In: Fang, E., Ng, T. (eds) Antitumor Potential and other Emerging Medicinal Properties of Natural Compounds. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6214-5_10

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