Ribosome-inactivating proteins: From plant defense to tumor attack

Toxins

Volumn 2, Issue 11, 2010, Pages 2699-2737

  de Virgilio, Maddalena ^a   Lombardi, Alessio ^b   Caliandro, Rocco ^c   Fabbrini, Maria Serena ^b  

^a Institute of Biosciences and Bioresources   (Italy)

^b CNR Consiglio Nazionale delle Ricerche   (Italy)

^c CNR   (Italy)

Author keywords

Cancer immunotherapy; Fusion toxins; Its; Pichia pastoris; Recombinant expression; Ribosome inactivating proteins; Single chain antibody variable fragments; Vascular leak syndrome

Indexed keywords

BASIC FIBROBLAST GROWTH FACTOR; BASIC FIBROBLAST GROWTH FACTOR SAPORIN; DENILEUKIN DIFTITOX; DIANTHIN; GELONIN; IMMUNOTOXIN; IMMUNOTOXIN DTAT; IMMUNOTOXIN DTAT13; IMMUNOTOXIN DTIL13; IMMUNOTOXIN RFB4; IMMUNOTOXIN VB6 845; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN; LYCHNIN; OKT 10 SAPORIN CD38 ANTIBODY CONJUGATE; PLASMID DNA; PLASMINOGEN ACTIVATOR INHIBITOR; POKEWEED ANTIVIRUS PROTEIN; PSEUDOMONAS EXOTOXIN; RECOMBINANT GELONIN CD33 MONOCLONAL ANTIBODY CONJUGATE; RECOMBINANT RICIN A TRANSFERRIN RECEPTOR MONOCLONAL ANTIBODY CONJUGATE; RIBOSOME INACTIVATING PROTEIN; RIBOSOME PROTEIN; RIBOSOME RNA; SAPORIN; SAPORIN 83; SAPORIN CD19 ANTIBODY CONJUGATE; SAPORIN CD30 ANTIBODY CONJUGATE; TRICHOSANTHES EXTRACT; TRICHOSANTHIN; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ACUTE LYMPHOBLASTIC LEUKEMIA; AMINO ACID SEQUENCE; ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; B CELL LYMPHOMA; BRAIN CANCER; CANCER GENE THERAPY; CATALYSIS; CYTOTOXICITY; DRUG DESIGN; DRUG DOSE ESCALATION; DRUG SYNTHESIS; ENZYME ACTIVITY; ESCHERICHIA COLI; FIBROSARCOMA; HEMATOLOGIC MALIGNANCY; HODGKIN DISEASE; HUMAN; IMMUNOGENICITY; LYMPHANGIOSARCOMA; MAMMAL CELL; MELANOMA; NONHUMAN; NONVIRAL GENE DELIVERY SYSTEM; OVARY CARCINOMA; PAIN; PLANT DEFENSE; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN INTERACTION; PROTEIN PROCESSING; REVIEW; SAPONARIA; SIDE EFFECT;

ANIMALS; ANTINEOPLASTIC AGENTS; DISEASE MODELS, ANIMAL; HUMANS; IMMUNOTOXINS; MICE; MOLECULAR SEQUENCE DATA; MOLECULAR TARGETED THERAPY; NEOPLASMS; PLANT DISEASES; PLANT PROTEINS; PROTEIN STRUCTURE, TERTIARY; RATS; RIBOSOME INACTIVATING PROTEINS; RICIN; SEQUENCE ANALYSIS, PROTEIN;

MAMMALIA; PICHIA PASTORIS; RATTUS;

EID: 79952171934     PISSN: None     EISSN: 20726651     Source Type: Journal    
DOI: 10.3390/toxins2112699     Document Type: Review

References (198)

1. Stirpe, F. Ribosome-inactivating proteins. Toxicon 2004, 44, 371-383.
2. Stirpe, F.; Battelli, M.G. Ribosome-inactivating proteins: Progress and problems. Cell. Mol. LifeSci. 2006, 44, 1850- 1866.
3. Wang, P.; Tumer, N.E. Virus resistance mediated by ribosome inactivating proteins. Adv. Virus Res. 2000, 55, 325-356.
4. Olsnes, S.; Pihl, A. Different biological properties of the two constituent peptide chains of ricin, atoxic protein inhibiting protein synthesis. Biochemistry 1973, 12, 3121-3126.
5. Lord, J.M.; Roberts, L.M.; Robertus, J.D. Ricin: Structure, mode of action, and some currentapplications. FASEB J. 1994, 8, 201-208.
6. Peumans, W.J.; Hao, Q.; Van Damme, E.J. Ribosome-inactivating proteins from plants: More than N-glycosidases? FASEB J. 2001, 15, 1493-1506.
7. Stirpe, F.; Barbieri, L. Ribosome-inactivating proteins up to date. FEBS Lett. 1986, 195, 1-8.
8. Kwon, S.Y.; An, C.S.; Liu, J.R.; Kwak, S-S.; Lee, H.S.; Lim, J.K.; Paek, K.H. Molecular cloning of a cDNA encoding ribosome-inactivating protein from Amaranthus viridis and its expression inE. coli. Mol. Cells 2000, 10, 8-12.
9. Lodge, J.K.; Kaniewski, W.K.; Tumer, N.E. Broad-spectrum virus resistance in transgenic plantsexpressing pokeweed antiviral protein. Proc. Natl. Acad. Sci. USA 1993, 90, 7089-7093.
10. Lam, Y.H.; Wong, Y.S.; Wang, B.; Wong, R.N.S.; Yeung, H.M.; Shaw, P.C. Use of trichosanthinto reduce infection by turnip mosaic virus. Plant Sci. 1996, 114, 111-117.
11. Moon, Y.H.; Song, S.K.; Choi, K.W.; Lee, J.S. Expression of a cDNA encoding Phytolacca insularisantiviral protein confers virus resistance of transgenic potato plants. Mol. Cells 1997, 7, 807-815.
12. Taylor, S.; Massiah, A.; Lomonossoff, G.; Roberts, L.M.; Lord, J.M.; Hartley, M. Correlation betweentheactivitiesoffiveribosome-inactivatingproteinsindepurinationoftobaccoribo-somes and inhibition of tobacco mosaic virus infection. Plant J. 1994, 5, 827-835.
13. Tarantini, A.; Pittaluga, E.; Marcozzi, G.; Testone, G.; Rodrigues-Pousada, R.A.; Giannino, D.; Spanò, L. Differential expression of saporin genes upon wounding, ABA treatment and leaf development. Physiol. Plant. 2010, 140, 141-152.
14. Carzaniga, R.; Sinclair, L.; Fordham-Skeleton, A.P.; Harris, N.; Croy, R.R.D. Cellular and subcellulardistributionofsaporins,typeIribosome-inactivatingproteins,insoapwort(Saponaria officinalis L.). Planta 1994, 194, 461-470.
15. Ready, M.; Brown D.T. Extracellular localization of pokeweed antiviral protein. Proc. Natl. Acad. Sci. USA 1986, 83, 5053-5056.
16. Roberts, L.M.; Lord, J.M. The synthesis of Ricinus communis agglutinin-cotranslational andposttranslational modification of agglutinin polypeptides. J. Eur. Biochem. 1981, 119, 31-41.
17. Nielsen, K.; Boston, R.S. Ribosome-inactivating proteins: A plant perspective. Annu. Rev. PlantPhysiol. Plant Mol. Biol. 2001, 52, 785-816.
18. Chan, A.; Crabtree, J.; Zhao, Q.; Lorenzi, H.; Orvis, J.; Puiu, D.; Melake-Berhan, A.; Jones, K.M.; Redman, J.; Chen, G.; Cahoon, E.B.; Gedil, M.; Stanke, M.; Haas, B.J.; Wortman, J.R.; Fraser-Liggett, C.M.; Ravel, J.; Rabinowicz, P.D. Draft genome sequence of the oilseed species Ricinus communis. Nat. Biotechnol. 2010, 28, 951-956.
19. Weeks, A.; Leshin, J.A.; Dretchen, K.L.; Skowronski, E.W.; O'Connel, K.P. Population-levelvariation of the preproricin gene contradicts expectation of neutral equilibrium for generalist plant defense toxins. Toxicon 2010, 55, 1475-1483.
20. Hartley, MR.; Lord, J.M. Cytotoxic ribosome-inactivating lectins from plants. Biochim. Biophys. Acta. 2004, 1701, 1-14.
21. Frigerio, L.; Jolliffe, N.A.; Di Cola, A.; Felipe, D.H.; Paris, N.; Neuhaus, J.M.; Lord, J.M.; Ceriotti, A.; Roberts, L.M. The internal propeptide of the ricin precursor carries a sequencespecific determinant for vacuolar sorting. Plant. Physiol. 2001, 126, 167-175.
22. Frigerio, L.; Vitale, A.; Lord, J.M.; Cerotti A.; Roberts, L.M. Free Ricin A chain, proricin, native toxin have different cellular fates when expressed in tobacco protoplasts. J. Biol. Chem. 1998, 273, 14194-14199.
23. Di Cola, A.; Frigerio, L.; Lord, J.M.; Ceriotti, A.; Roberts, L.M. Ricin A chain without its partner B chain is degraded after retrotranslocation from the endoplasmic reticulum to the cytosol in the plant cells. Proc. Natl. Acad. Sci. USA 2001, 98, 14726-14731.
24. Vitale, A.; Boston, R.S. Endoplasmic reticulum quality control and the unfolded protein response: Insights from plants. Traffic 2008, 9, 1581-1588.
25. Marshall, R.S.; Jolliffe, N.A.; Ceriotti, A.; Snowden, C.J.; Lord, J.M.; Frigerio, L.; Roberts, L.M. The role of CDC48 in the retro-translocation of non-ubiquitinated toxin substrates in plant cells. J. Biol. Chem. 2008, 283, 15869-15877.
26. Prestle, J.; Schönfelder, M.; Adam, G.; Mundry, K.-W. Type 1 ribosome-inactivating proteins depurinate plant 25S rRNA without species specificity. Nucl. Acid. Res. 1992, 20, 3179-3182.
27. Bonness, M.S.; Ready, M.P.; Irvin J.D.; Mabri, T.J. Pokeweed antiviral protein inactivates pokeweed ribosomes; implications for the antiviral mechanism. Plant J. 1994, 5, 173-183.
28. Kataoka, J.; Habuka, N.; Miyano, M.; Masuta, C.; Koiwai, A. Adenine depurination andinactivation of plant ribosomes by an antiviral protein of Mirabilis jalapa (MAP). Plant Mol. Biol. 1992, 20, 1111-1119.
29. Vandenbussche, F.; Peumans, W.J.; Desmyter, S.; Proost, P.; Ciani, M.; Van Damme, E.J. The type 1 and type 2 ribosome-inactivating proteins from Iris confer transgenic tobacco plants local but not systemic protection against viruses. Planta 2004, 220, 211-221.
30. Desvoyes, B.; Proyet, J.L.; Schlik, J.L.; Adami, P.; Jouvenot, M.; Dulieu, P. Identification of a biological inactive complex from a pokeweed antiviral protein. FEBS Lett. 1997, 410, 303-308.
31. Marshall, R.S.; D'Avila, F.; Di Cola, A.; Traini, R.; Spanò, L.; Fabbrini, M.S.; Ceriotti, A. Signal peptide-regulated toxicity of a plant ribosome inactivating protein during cell stress. PlantJ. 2010, in press.
32. Kang, S.W.; Rane, N.S.; Kim, S.J.; Garrison, J.L.; Taunton, J.; Hegde, R.S. Substrate-specifictranslocational attenuation during ER stress defines a pre-emptive quality control pathway. Cell 2006, 127, 999-1013.
33. Lombardi, A.; Marshall, R.S.; Savino, C.; Fabbrini, M.S.; Ceriotti, A. Toxic Plant Proteins, Plant Cell Monographs; Lord, J.M., Hartley, M.R., Eds.; Springer-Verlag: Berlin/Heidelberg, Germany, 2010; Volume 18, Chapter 4, p. 55.
34. Fabbrini, M.S.; Rappocciolo, E.; Carpani, D.; Solinas, M.; Valsasina, B.; Breme, U.; Cavallaro, U.; Nikjaer, A.; Rovida, E.; Legname, G.; Soria, M.R. Characterization of a saporin isoform with lower ribosome-inhibiting activity. Biochem. J. 1997, 322, 719-727.
35. Rosenblum, M.G.; Kohor, W.A.; Beattie, K.L.; Beattie, W.G.; Marks, J.W.; Toman, P.D.; Cheung, L.H. Amino acid sequence analysis, gene construction, cloning, and expression of gelonin, a toxin derived from Gelonium multiflorum. J. Interf. Cytok. Res. 1995, 15, 547-555.
36. Montfort, W.; Villafranca, J.E.; Monzingo, A.F.; Ernst, S.R.; Katzin, B.; Rutenber, E.; Xuong, N.H.; Hamlin, R.; Robertus, J.D. The three-dimensional structure of ricin at 2.8 Å. J. Biol. Chem. 1987, 262, 5398-5403.
37. Monzingo, A.F.; Collins, E.J.; Ernst, S.R.; Irwin, J.D.; Robertus, J.D. The 2.5 Å structure ofpokeweed antiviral protein. J. Mol. Biol. 1993, 233, 705-715.
38. Zhou, K.; Fu, Z.; Chen, M.; Lin, Y.; Pan, K. Structure of trichosanthin at 1.88 Å resolution. Proteins 1994, 19, 4-13.
39. Hosur, M.V.; Nair, B.; Satyamurthy, P.; Misquith, S.; Surolia, A.; Kannan, K.K. X-ray structureof gelonin at 1.8 Å resolution. J. Mol. Biol. 1995, 250, 368-380.
40. Savino, C.; Federici, L.; Ippoliti, R.; Lendaro, E.; Tsernoglou, D. The crystal structure of saporinSO6 from Saponaria officinalis and its interaction with the ribosome. FEBS Lett. 2000, 470, 239-243.
41. Fermani, S.; Falini, G.; Ripamonti, A.; Polito, L.; Stirpe, F.; Bolognesi, A. The 1.4 Å structure ofdianthin 30 indicates a role of surface potential at the active site of type 1 ribosome-inactivating proteins. J. Struct. Biol. 2005, 149, 204-212.
42. Weston, S.A.; Tucker, A.D.; Thatcher, D.R.; Derbyshire, D.J.; Pauptit, R.A. X-ray structure ofrecombinant ricin A-chain at 1.8 Å resolution. J. Mol. Biol. 1994, 244, 410-422.
43. Vater, C.A.; Bartle, L.M.; Leszyk, J.D.; Lambert, J.M.; Goldmacher, V.S. Ricin A chain can bechemically crosslinked to the mammalian ribosomal proteins L9 and L10e. J. Biol. Chem. 1995, 270, 12933-12940.
44. Hudak, K.A.; Dinman, J.D.; Tumer, N.E. Pokeweed antiviral protein accesses ribosomes by binding to L3. J. Biol. Chem. 1999, 274, 3859-3864.
45. Ippoliti, R.; Lendaro, E.; Bellelli, A.; Brunori, M. A ribosomal protein is specifically recognizedby saporin, a plant toxin which inhibits protein synthesis. FEBS Lett. 1992, 298, 145-148.
46. McCluskey, A.J.; Poon, G.M.K.; Bolewska-Pedyczak, E.; Srikumar, T.; Jeram, S.M.; Raught, B.; Gariepy, J. The catalytic subunit of Shiga-like toxin 1 interacts with ribosomal stalk proteins and is inhibited by their conserved C-terminal domain. J. Mol. Biol. 2008, 378, 375-386.
47. Korennykh, A.V.; Correll, C.C.; Piccirilli, A.J. Evidence for the importance of electrostatics inthe function of two distinct families of ribosome inactivating toxins. RNA 2007, 13, 1391-1396.
48. Endo, Y. Mechanism of action of ricin and related toxins on the inactivation of eukaryoticribosomes. Canc. Treat. Res. 1988, 37, 75-89.
49. Endo, Y.; Tsurugi, K.; Lambert, J.M. The site of action of six different ribosome-inactivatingproteins from plants on eukaryotic ribosomes. The RNA N-glycosidase activity of the proteins. Biochem. Biophys. Res. Commun. 1988, 150, 1032-1036.
50. Barbieri, L.; Gorini, P.; Valbonesi, P.; Castiglioni, P.; Stirpe, F. Unexpected activity of saporins. Nature 1994, 372, 624.
51. Barbieri, L.; Valbonesi, P.; Bonora, E.; Gorini, P.; Bolognesi, A.; Stirpe, F. Polynucleotide:adenosine glycosidase activity of ribosome-inactivating proteins: Effect on DNA, RNA and poly(A). Nucl. Acid. Res. 1997, 25, 518-522.
52. Bagga, S.; Seth, D.; Batra, J.K. The cytotoxic activity of ribosome-inactivating protein saporin-6is attributed to its rRNA N-glycosidase and internucleosomal DNA fragmentation activities. J. Biol. Chem. 2003, 278, 4813-4820.
53. Zarovni, N.; Vago, R.; Soldà, T.; Monaco, L.; Fabbrini, M.S. Saporin as a novel suicide gene in anticancer gene therapy. Canc. Gene Ther. 2007, 14, 165-173.
54. Lombardi, A.; Bursomanno, S.; Lopardo, T.; Traini, R.; Colombatti, M.; Ippoliti, R.; Flavell, D.J.; Flavell, S.U.; Cerotti, A.; Fabbrini, M.S. Pichia pastoris as a host for secretion of toxic saporin chimeras. FASEB J. 2010, 24, 253-265.
55. Rajamohan, F.; Pugmire, M.J.; Kurinov, I.V.; Uckun, F.M. Modeling and alanine scanning mutagenesis studies of recombinant pokeweed antiviral protein. J. Biol. Chem. 2000, 275, 3382-3390.
56. Hudak, K.A.; Wang, P.; Tumer, N.E. A novel mechanism for inhibition of translation by pokeweed antiviral protein: Depurination of the capped RNA template. RNA 2000, 6, 369-380.
57. Roncuzzi, L.; Gasperi-Campani, A. DNA-nuclease activity of single-chain ribosome-inactivating proteins dianthin 30, saporin 6 and gelonin. FEBS Lett. 1996, 392, 16-20.
58. Nicolas, E.; Beggs J.M.; Haltiwanger, B.M.; Taraschi, T.F. A new class of DNA glycosylase/ apurinic/ apyrimidinic lyases that act on specific adenines in single-stranded DNA.J. Biol. Chem. 1998, 273, 17216-1720.
59. Fermani, S.; Tosi, G.; Farini, V.; Polito, L.; Falini, G.; Ripamonti, A.; Barbieri, L.; Chambery, A.; Bolognesi, A. Structure/function studies on two type 1 ribosome inactivating proteins: Bouganin and Lychinin. J. Struct. Biol. 2009, 168, 278-287.
60. Li, X.-D.; Chen, W.-F.; Liu, W.-Y.; Wang, G.-H. Large-scale preparation of two new ribosome- inactivating proteins, Cinnamomin and Camphorin, from the seeds of Cinnamomum camphora. Protein Expr. Purif. 1997, 10, 27-31.
61. Helmy, M.; Lombard, S.; Pieroni, G. Ricin RCA60: Evidence of its phospholipase activity. Biochem. Biophys. Res. Commun. 1999, 258, 252-255.
62. Sharma, N.; Park, S-W.; Vepachedu, R.; Barbieri, L.; Ciani, M.; Stirpe, F.; Savary, B.J.; Vivanco, J.M. Isolation and characterization of a RIP-like protein from Nicotiana tabacum with dual enzymatic activity. Plant Physiol. 2004, 134, 171-181.
63. Sturm, M.B.; Tyler, P.C.; Evans, G.B.; Schramm, V.L. Transition state analogues rescue ribosomes from saporin L1 ribosome inactivating protein. Biochemistry 2009 48, 9941-9948.
64. Vago, R.; Marsden, C.J.; Lord, J.M.; Ippoliti, R.; Flavell, D.J.; Flavell, S.U.; Ceriotti A.; Fabbrini, M.S. Saporin and ricin A chain follow different intracellular routes to enter the cytosol of intoxicated cells. FEBS J. 2005, 272, 4983-4995.
65. Day, P.J.; Lord, JM.; Roberts, L.M. The deoxyribonuclease activity attributed to ribosomeinactivating proteins is due to contamination. Eur. J. Biochem. 1998, 258, 540-545.
66. Barbieri, L.; Valbonesi, P.; Righi, F.; Zucceri, G.; Monti, F.; Gorini, P.; Samori, B.; Stirpe, F.Polynucleotide: Adenosine glycosidase is the sole activity of ribosome-inactivating proteins DNA. J. Biochem. 2000, 128, 883-889.
67. Sandvig, K.; van Deurs, B. Delivery into cells: Lessons learned from plant and bacterial toxins. Gene Ther. 2005, 12, 865-872.
68. Spooner, R.A; Watson, P.D; Marsden, C.J.; Smith, D.C.; Moore, K.A.H.; Cook, J.P.; Lord J.M.; Roberts, L.M. Protein disulphide isomerase reduces ricin to its A and B chains in the endoplasmic reticulum. Biochem. J. 2004, 383, 285-293.
69. Deeks, E.D.; Cook, J.P.; Day, P.J.; Smith, D.C.; Roberts, L.M.; Lord, J.M. The low lisine content of ricin A chain reduces the risk of proteolytic degradation after translocation from the endoplasmic reticulum to the cytosol. Biochemistry. 2002, 41, 3405-3413.
70. Lillis, A.P.; Van Duyn, L.B.; Murphy-Ullrich, J.E.; Strickland, D.K. LDL Receptor Related Protein 1: Unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 2008, 88, 887-918.
71. Rajagopal, V.; Kreitman, J.K. Recombinant toxins that bind to the urokinase receptor are cytotoxic without requiring binding to the a2-macroglobulin receptor. J. Biol. Chem. 2000, 275, 7566-7573.
72. Fabbrini, M.S.; Carpani, D.; Bello-Rivero, I.; Soria, M.R. The amino-terminal fragment ofhumanurokinasedirectsarecombinantchimerictoxintotarget cells:Internalization is toxin-mediated. FASEB J. 1997, 11, 1169-1176.
73. Ippoliti, R.; Lendaro, E.; Benedetti, P.A.; Torrisi, MR.; Belleudi, F.; Carpani, D.; Soria, MR.; Fabbrini, M.S. Endocytosis of a chimera between human pro-urokinase and the plant toxin saporin: An unusual internalization mechanism. FASEB J. 2000, 14, 1335-1344.
74. Wales, R.; Roberts, L.M.; Lord, J.M. Addition of an endoplasmic reticulum retrieval sequence to ricin A chain significantly increases its cytotoxicity to mammalian cells. J. Biol. Chem. 1993, 268, 23986-23990.
75. Geden, S.; Gardner, R.; Fabbrini, M.S.; Ohashi, M.; Phanstiel, I.O.; Teter, K. Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate. FEBS J. 2007, 274, 4825-4836.
76. Fabbrini, M.S.; Carpani, D.; Soria M.R.; Ceriotti, A. Cytosolic immunization allows theexpression of preATF-saporin chimeric toxin in eukaryotic cells. FASEB J. 2000, 14, 391-398.
77. Zhang, F; Sun, S; Feng, D; Zhao, W.L.; Sui, S.F. A novel strategy for the invasive toxin: Hijacking exosome-mediated intercellular trafficking. Traffic 2009, 10, 411-424.
78. Chan, W.L.; Shaw, P.C.; Tam, S.C.; Jacobsen, C.; Gliemann, J.; Nielsen, M.S. Trichosanthin interacts with and enters cells via LDL receptor family members. Biochem. Biophys. Res. Commun. 2000, 270, 453-457.
79. Rosenblum, M.G.; Cheung, L.H.; Liu, Y.; Marks, J.W. Design, expression, Purification and characterization, in vitro and in vivo, of an antimelanoma single-chain Fv antibody fused to the toxin gelonin. Canc. Res. 2003, 63, 3995-4002.
80. Vallera, D.A.; Oh, S.; Chen, H.; Shu, Y.; Frankel, A.E. Bioengineering a unique deimmunizedbispecific targeted toxin that simultaneously recognizes human CD22 and CD19 receptors in a mouse model of B-cell metastases. Mol. Canc. Ther. 2010, 9, 1872-1883.
81. Amessou, M.; Fradagrada, A.; Falguières, T.; Lord J.M.; Smith, D.C.; Roberts, L.M.; Lamaze, C.; Johannes, L. Syntaxin 16 and syntaxin 5 are required for efficient retrograde transport of several exogenous and endogenous cargo proteins. J. Cell Sci. 2007, 120, 1457-1468.
82. Wesche, J.; Rapak, A.; Olsnes, S. Dependence of ricin toxicity on translocation of the toxin A-chain from the endoplasmic reticulum to the cytosol. J. Biol. Chem. 1999, 274, 34443-34449.
83. Mayerhofer, P.U.; Cook J.P.; Wahlman, J.; Pinheiro, T.T.; Moore, K.A.; Lord, J.M.; Johnson, A.E.; Roberts, L.M. Ricin A chain insertion into endoplasmic reticulum membranes is triggered by a temperature increase to 37 oC. J. Biol. Chem. 2009, 284, 10232-10242.
84. Li, S.; Spooner, R.A.; Allen, S.C.; Guise, C.P.; Ladds, G.; Schnöder, T.; Schmitt, M.J.; Lord J.M.; Roberts, L.M. Folding-competent and folding-defective forms of ricin A chain may have different fates. Mol. Biol. Cell. 2010, 21, 2543-2554.
85. Spooner, R.A.; Hart, P.J.; Cook, J.P.; Pietroni, P.; Rogon, C.; Höhfeld, J.; Roberts, L.M.; Lord, J.M. Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 2008, 105, 17408-17413.
86. Austin, C.D.; Wen, X.; Gazzard, L.; Nelson, C.; Scheller, R.H.; Scales, S.J. Oxidizing potentialof endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates. Proc. Natl. Acad. Sci. USA 2005, 102, 17987-17992.
87. Bellisola, G.; Fracasso, G.; Ippoliti, R.; Menestrina, G.; Rosén, A.; Soldà, S.; Udali, S.; Tomazzolli, R.; Tridente, G.; Colombatti, M. Reductive activation of ricin and ricin A-chain immunotoxins by protein disulfide isomerase and thioredoxin reductase. Biochem. Pharmacol. 2004, 67, 1721-1731.
88. Zarling, J.M.; Moran, P.A.; Haffar, O.; Sias, J.; Richman, D.D.; Spina, C.A.; Myers, D.E.; Kuebelbeck, V.; Ledbetter, J.A.; Uckun, F.M. Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies. Nature 1990, 347, 92-95.
89. McGrath, M.S.; Hwang, K.M.; Caldwell, S.E.; Gaston, I.; Luk, K.C.; Wu, P.; Ng, W.L.; Crowe, S.; Daniels, J.; Marsh, J. GLQ223: An inhibitor of human immunodeficiency virus replication in acutely and chronically infected cells of lymphocyte and mononuclear phagocyte lineage. Proc. Natl. Acad. Sci. USA. 1989, 86, 2844-2848.
90. Byers, V.S.; Levin, A.S.; Malvino, A.; Waites, L.A; Robins, R.A.; Baldwin, R.W. A phase IIstudy of effect of addition of trichosanthin to zidovudine in patients with HIV disease and failing antiretroviral agents. AIDS Res. Hum. Retrovir. 1994, 10, 413-420.
91. Yeung, H.W.; Li, W.W.; Feng, Z.; Barbieri, L.; Stirpe, F. Trichosanthin, alpha-momorcharin and beta-momorcharin: Identity of abortifacient and ribosome-inactivating proteins. Int. J. Pept. Protein Res. 1988, 31, 265-268.
92. Battelli, M.G.; Mantacuti, V.; Stirpe, F. High sensitivity of cultured human trophoblasts toribosome-inactivating proteins. Exp. Cell Res. 1992, 201, 109-112.
93. Audi, J.; Belson, M.; Patel, M.; Schier, J.; Osterloh, J. Ricin poisoning: A comprehensive review. JAMA 2005, 294, 2342-2351.
94. Fredriksson, S.A.; Hulst, A.G.; Artursson, E.; de Jong, A.L.; Nilsson, C.; van Baar, B.L. Forensicidentification of neat ricin and of ricin from crude castor bean extracts by mass spectrometry. Anal. Chem. 2005, 77, 1545-1555.
95. Rubina, A.Y.; Dyukova, V.I.; Dementieva, E.I.; Stomakhin, A.A.; Nesmeyanov, V.A.; Grishin, E.V.; Zasedatelev, A.S. Quantitative immunoassay of biotoxins on hydrogelbased protein microchips. Anal. Biochem. 2005, 340, 317-329.
96. Guo, J.W.; Shen, B.F.; Feng, J.N.; Sun, Y.X.; Yu, M.; Hu, M.R. A novel neutralizing monoclonalantibody against cell-binding polypeptide of ricin. Hybridoma (Larchmt) 2005, 24, 263-266.
97. Vitetta, E.S.; Smallshaw, J.E.; Coleman, E.; Jafri, H.; Foste, C.; Munford, R.; Schindler, J.A pilot clinical trial of a recombinant ricin vaccine in normal humans. Proc. Natl. Acad. Sci. USA 2006, 103, 2268-2273.
98. Marconescu, P.S.; Smallshaw, J.E.; Pop, L.M.; Ruback, S.L.; Vitetta, E.S. Intradermal administration of RiVax protects mice from mucosal and systemic ricin intoxication. Vaccine 2010, 28, 5315-5322.
99. Campoli, M.; Ferris, R.; Ferrone, S.; Wang, X. Immunotherapy of malignant disease with tumorantigen-specific monoclonal antibodies. Clin. Canc. Res. 2010, 16, 11-20.
100. Fracasso, G.; Stirpe, F.; Colombatti, M. In Toxic Plant Proteins, Plant Cell Monographs; Lord, J.M., Hartley, M.R., Eds.; Springer-Verlag: Berlin/Heidelberg, Germany, 2010; Volume 18, Chapter 12, p. 225.
101. Huston, J.S.; Mudgett-Hunter, M.; Tai, M.S.; McCartney, J.; Warren, F.; Haber, E.; Oppermann, H. Protein engineering of single-chain Fv analogs and fusion proteins. Meth. Enzymol. 1991, 203, 46-88.
102. Huston, J.S.; Tai, M.S.; McCartney, J.; Keck, P.; Oppermann, H. Antigen recognition andtargeted delivery by the single-chain Fv. Cell Biophys. 1993, 22, 189-224.
103. Kreitman, R.J. Recombinant immunotoxins containing truncated bacterial toxins for the treatment of hematologic malignancies. BioDrugs 2009, 23, 1-13.
104. Kreitman, R.J. Toxin-labeled monoclon alantibodies. Curr.Pharm.Biotechnol.2001, 2 313-325.
105. Pastan, I.; Hassan, R.; Fitz Gerald, D.J.; Kreitman, R.J. Immunotoxin treatment of cancer. Annu. Rev. Med. 2007, 58, 221-237.
106. Savage, P; Rowlinson-Busza, G.; Verhoeyen, M.; Spooner, R.A.; So, A.; Windust, J.; Davis, P.J.; Epenetos, A.A. Construction, characterisation and kinetics of a single chain antibody recognisingthe tumour associated antigen placental alkaline phosphatase. Br. J. Canc. 1993, 68, 738-742.
107. Batra, S.K.; Jain, M.; Wittel, U.A.; Chauhan, S.C.; Colcher, D. Pharmacokinetics and biodistribution of genetically engineered antibodies. Curr. Opin. Biotechnol. 2002, 13, 603-608.
108. Jain, M.; Chauhan, S.C.; Singh, A.P.; Venkatraman, G.; Colcher, D.; Batra, S.K. Penetratinimproves tumor retention of single-chain antibodies: A novel step toward optimization of radioimmunotherapy of solid tumors. Canc. Res. 2005, 65, 7840-7846.
109. Fabbrini, M.S.; Flavell, D.J.; Ippoliti, R. In Bacterial Plant and Animal Toxins; Ascenzi, P., Polticelli, F., Visca, P., Eds.; Research Signpost: Kerala, India, 2003; Chapter 4, p. 69.
110. Amlot, P.L.; Stone, M.J.; Cunningham, D.; Fay, J.; Newman, J.; Collins, R.; May, R.; McCarthy, M.; Richardson, J.; Ghetie, V.; et al. 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 1993, 82, 2624-2633.
111. Falini, B.; Bolognesi, A.; Flenghi, L.; Tazzari, P.L.; Broe, M.K.; Stein, H.; Dürkop, H.; Aversa, F.; Corneli, P.; Pizzolo, G.; et al. Response of refractory Hodgkin's disease to monoclonal anti-CD30 immunotoxin. Lancet 1992, 16, 339, 1195-1196.
112. Flavell, D.J.; Noss, A.; Pulford, K.; Flavell, S. Systemic therapy with 3BIT, a triple combination cocktail of anti-CD19, -CD22, and -CD38-saporin immunotoxins, is curative of human B-celllymphoma in severe combined immunodeficient mice. Canc. Res. 1997, 57, 4824-4829.
113. Laske, D.W.; Muraszko, K.M.; Oldfield, E.H.; DeVroom, H.L.; Sung, C.; Dedrik, R.L.; Simon, T.R.; Colandrea, J.; Copeland, C.; Katz, D.; Greenfield, L.; Grooves, E.S.; Houston, L.L.; Youle, R.J. Intraventricular immunotoxin therapy for leptomeningeal neoplasia. Neurosurgery 1997, 41, 1039-1049.
114. Pagliaro, L.C.; Liu, B.; Bunker, R.; Andreef, M.; Freireich, E.J.; Scheinberg, D.A.; Rosenblum,M.G. Humanized M195 monoclonal antibody conjugated to recombinant gelonin: An anti-CD33immunotoxin with antileukemic activity. Clin. Canc. Res. 1998, 4, 1971-1976.
115. Pennell, C.A.; Pauza, M.E. CD7-specific single chain Fv immunotoxins. Design and expression. Meth. Mol. Biol. 2001, 166, 17-29.
116. Chignola, R.; Anselmi, C.; Dalla Serra, M.; Franceschi, A.; Fracasso, G.; Pasti, M.; Chiesa, E.; Lord, J.M.; Tridente, G.; Colombatti, M. Self-potentiation of ligand-toxin conjugates containingricin A chain fused with viral structures. J. Biol. Chem. 1995, 270, 23345-23351.
117. Tazzari, P.L.; Polito, L.; Bolognesi, A.; Pistillo, M.P.; Capanni, P.; Palmisano, GL.; Lemoli, R.M.; Curti, A.; Biancone, L.; Camussi, G.; Conte, R.; Ferrara, G.B.; Stirpe F. Immunotoxins containing recombinant anti-CTLA-4 single-chain fragment variable antibodies and saporin: in vitro results and in vivo effects in an acute rejection model. J. Immunol. 2001, 167, 4222-4229.
118. Piazza, T.; Cha, E.; Bongarzone, I.; Canevari, S.; Bolognesi, A.; Polito, L.; Bargellesi, A.; Sassi, F.; Ferrini, S.; Fabbi, M. Internalization and recycling of ALCAM/CD166 detected by a fully human single-chain recombinant antibody. J. Cell Sci. 2005, 118, 1515-1525.
119. Fuchs, H.; Bachran, C.; Li, T.; Heisler, I.; Durkop, H.; Sutherland, M. A cleavable molecular adapter reduces side effects and concomitantly enhances efficacy in tumor treatment by targeted toxins in mice. J. Control. Release 2007, 117, 342-350.
120. O'Hare, M.; Brown, A.N.; Hussain, K.; Gebhardt, A.; Watson, G.; Roberts, L.M. Cytotoxicity ofa recombinant ricin-A-chain fusion protein contain a proteolytically-cleavable spacer sequence. FEBS Lett. 1990, 273, 200-204.
121. Hartley, M.R.; Legname, G.; Osborn, R.; Chen, Z.; Lord, J.M.S. Single chain ribosomeinactivating proteins from plants depurinate Escherichia coli 23S ribosomal RNA. FEBS Lett. 1991, 290, 65-68.
122. Chaddock, J.A; Lord, J.M; Hartley, M.R; Roberts, L.M. Pokeweed antiviral protein (PAP)mutations which permit E. coli growth do not eliminate catalytic activity towards prokaryotic ribosomes. Nucl. Acid. Res. 1994, 22, 1536-1540.
123. Kataoka, J.; Ago, H.; Habuka, N.; Furano, M.; Masuta, C.; Miyano, M.; Koiwai, A. Expressionof a pokeweed antiviral protein in Escherichia coli and its characterization. FEBS Lett. 1990, 320, 31-34.
124. Liu, L.; Wang, R.; He, W.; He, F.; Huang, G. Cloning and soluble expression of mature α-luffinfrom Luffa cylindrica and its antitumor activities in vitro. Acta Biochim. Biophys. Sin. (Shanghai) 2010, 42, 585-592.
125. Huang, J.; Villemain, J; Padilla, R; Sousa, R. Mechanisms by which T7 lysozyme specificallyregulates T7 RNA polymerase during different phases of transcription. 1999, J. Mol. Biol. 293, 457-475.
126. Giansanti, F.; Di Leandro, L.; Koutris, I.; Pitari G.; Fabbrini, M.S.; Lombardi, A.; Flavell, D.J.; Flavell, S.U.; Gianni, S.; Ippoliti, R. Engineering a switchable toxin: The potential use of PDZ domains in the expression, targeting and activation of modified Saporin variants. Protein Eng. Des. Sel. 2010, 23, 61-68.
127. Pitcher, C.; Roberts, L; Fawell, S.; Zdanovsky, A.G.; FitzGerald, D.J.; Lord, J.M. Generation of apotent chimeric toxin by replacement of domain III of Pseudomonas exotoxin with ricin A chain KDEL. Bioconjug. Chem. 1995, 6, 624-629.
128. Dore, J.M.; Gras, E.; Wijdenes, J. Expression and activity of a recombinant chimeric protein composed of pokeweed antiviral protein and of human interleukin-2. FEBS Lett. 1997, 402, 50-52.
129. Qi, L.; Nett, T.M.; Allen, M.C.; Sha, X.; Harrison, G.S.; Federick, B.A.; Crawford, E.D.; Glode, L.M. Binding and cytotoxicity of conjugated and recombinant fusion proteins targeted tothe Gonadotropin-releasing hormone receptor. Canc. Res. 2004, 64, 2090-2095.
130. Lappi, D.A.; Ying, W.; Barthelemy, I.; Martineau, D.; Prieto, I.; Benatti, L.; Soria, M.R.; Baird, A. Expression and activities of a recombinant basic fibroblast growth factor-saporin fusion protein. J. Biol. Chem. 1994, 269, 12552-12558.
131. Davol, P.A.; Beitz, J.G.; Mohler, M.; Ying, W.; Cook, J.; Lappi, D.A.; Frackelton, A.R., Jr.Saporin toxins directed to basic fibroblast growth factor receptors effectively target human ovarian teratocarcinoma in an animal model. Cancer 1995, 76, 79-85.
132. Davol, P.A.; Garza, S.; Frackelton, A.R., Jr. Combining suramin and a chimeric toxin directed tobasic fibroblast growth factor receptors increases therapeutic efficacy against human melanoma in an animal model. Cancer 1999, 86, 1733-1741.
133. Chandler, L.A.; Sosnowski, B.A.; McDonald, J.R.; Price, J.E.; Aukerman, S.L.; Baird A.; Pierce, G.F.; Houston, L.L. Targeting tumor cells via EGF receptors: Selective toxicity of an HBEGF-toxin fusion protein. Int. J. Canc. 1998, 78, 106-111.
134. Ellis, V.; Scully, M.F.; Kakkar, V.V. Plasminogen activation initiated by single-chain urokinase- type plasminogen activator. Potentiation by U937 monocytes. J. Biol. Chem.1989,264, 2185-2188.
135. Ragno, P. The urokinase receptor ligand: A ligand or a receptor? Story of a sociable molecule. Cell. Mol. Life Sci. 2006, 63, 1028-1037.
136. Stephens, R.W.; Nielsen, H.J.; Christensen, I.J.; Thorlacius-Ussing, O.; SØrensen, S.; DanØ, K.; Brünner, N. Plasma urokinase receptor levels in patients with colorectal cancer: Relationship to prognosis. J. Natl. Canc. Inst. 1999, 91, 869-874.
137. Mustijoki, S.; Alitalo, R.; Stephens, R.W.; Vaheri, A. Blast cell-surface and plasma solubleurokinase receptor in acute leukaemia patients: relationship to classification and response to therapy. Thromb. Haemost. 1999, 81, 705-710.
138. Sier, C.F.; Sidenius, N.; Mariani, A.; Aletti, G.; Agape, V.; Ferrai, A.; Casetta, G.; Stephens, R.W.; Brünner, N.; Blasi, F. Presence of urokinase-type plasminogen activator receptor in urine ofcancer patients and its possibile clinical relevance. Lab. Invest. 1999, 79, 717-722.
139. Rasch, M.G.; Lund, I.K.; Almasi, C.E.; HØyer-Hansen, G. Intact and cleaved uPAR forms: Diagnostic and prognostic value in cancer. Front. Biosc. 2008, 13, 6752-6762.
140. Degryse, B.; Fernandez-Recio, J.; Citro, V.; Blasi, F.; Cubellis, M.V. In silico docking ofurokinase plasminogen activator and integrins. BMC Bioinform. 2008, 9, S8.
141. Potala, S.; Sahoo, S.K.; Verma, R.S. Target therapy of cancer using diphtheria toxin-derivedimmunotoxins. Drug. Discov. Today 2008, 13, 809-815.
142. Vallera, D.A.; Li, C.; Jin, N.; Panoskaltis-Mortari, A.; Hall, W.A. Targeting urokinase-typeplasminogen activator receptor on human glioblastoma tumors with diphtheria toxin fusion protein DTAT. J. Nat Canc. Inst. 2002, 94, 597-606.
143. Ramage, J.G.; Vallera, D.A.; Black, J.H.; Aplan, P.D.; Kees, U.R.; Frankel, A.E. The diphtheriatoxin/urokinase fusion protein (DTAT) is selectively toxic to CD87 expressing leukemic cells. Leuk. Res. 2003, 27, 79-84.
144. Rustamzadeh, E.; Hall, W.A.; Todhunter, D.A.; Vallera, V.D.; Low, W.C.; Liu, H.; Panoskaltis- Mortari, A.; Vallera, A. Intracranial therapy of glioblastoma with the fusion protein DTAT in immunodeficient mice. Int. J. Canc. 2007, 120, 411-419.
145. Todhunter, D.A.; Mhall, W.A; Rustamzedeh, E.; Shu, Y; Doumbia, S.O; Vallera, D.A. Abispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model. Protein Eng. Des. Sel. 2004, 17, 157-164.
146. Rustamzadeh, E.; Vallera, D.A.; Todhunter, D.A.; Low, W.C.; Panoskaltis-Mortari, A.; Hall, W.A. Immunotoxin pharmacokinetics: a comparison of the anti-glioblastoma bi-specific fusion protein (DTAT13) to DTAT and DTL13. J. Neurooncol. 2006, 77, 257-266.
147. Frankel, AE. Reducing the Immune Response to Immunotoxin. Clinic. Canc. Res. 2004, 10, 16-18.
148. Hall, P.D.; Virella, G.; Willoughby, T.; Atchley, D.H.; Kreitman, R.J.; Frankel, A.E. AntibodyResponse to DT-GM, a novel fusion toxin consisting of truncated diphtheria toxin (DT) linked to human granulocyte-macrophage colony stimulating factor (GM), during a phase I trial of patient with relapsed or refractory acute myeloid leukaemia. Clin. Immunol. 2001, 100, 191-199.
149. Deckert, P.M. Current constructs and targets in clinical development for antibody-based cancer therapy. Curr. Drugs Targets 2009, 10, 158-175.
150. Carter, P.J.; Senter, P.D. Antibody-drug conjugates for cancer therapy. Canc. J.2008, 14, 154-169.
151. Whitlow, M.; Bell, B.A.; Feng, S.L.; Filpula, D.; Hardman, K.D.; Hubert, S.L.; Rollence, M.L.; Wood, J.F.; Schott, M.E.; Milenic, D.E.; Yokota, T.; Schlom, J. An improved linker forsingle-chain Fv with reduced aggregation and enhanced proteolytic stability. Protein Eng. 1993,6, 989-995.
152. Kim, J.H.; Weaver, R.F. Constructionofarecombinantexpressionplasmidencodingastaphylococcal protein A-ricin A fusion protein. Gene 1988, 68, 315-321.
153. Cao, Y.; Marks, J.D.; Marks, J.W.; Cheung, L.H.; Sehoon, K.; Rosenblum, M.G. Constructionand characterization of novel, recombinant immunotoxins targeting the Her2/neu oncogene product: in vitro and in vivo studies. Canc. Res. 2009, 69, 8987-8995.
154. Nimmanapalli, R.; Lyu, M-A.; Du, M.; Keating, M.J.; Rosenblum, M.G.; Gandhi, V. The growthfactor fusion construct containing B-lymphocyte stimulator (BLyS) and the toxin rGel inducesapoptosis specifically in BAFF-R-positive CLL cells. Blood 2007, 109, 2557-2564.
155. Lyu, M-A.; Cheung, L.H.; Hittelman, W.N.; Marks, J.W.; Aguiar, R.C.; Rosenblum, M.G. The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptorsBAFF-R, TACI, and BCMA. Mol. Canc. Ther. 2007, 6, 460-470.
156. 111In-labeled rGel/BLyS fusion toxin in SCID mice bearing B cell lymphoma. Mol. Imag. Biol. 2010, in press.
157. Lyu, M.-A.; Rai, D.; Ahn, K.S.; Sung, B.; Cheung, L.H.; Marks, J.W.; Aggarwall, B.B.; Aguiar, R.C.T.; Gandhi, V.; Rosenblum, M.G. The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo. Neoplasia 2010, 12, 366-375.
158. Thorpe, PE. Vascular targeting agents as cancer therapeutics Clin. Canc. Res.2004,10, 415-427.
159. Kim, S.; Mohamedali, K.A.; Cheung, LH.; Rosenblum, M.G. Overexpression of biologicallyactive VEGF121 fusion proteins in Escherichia coli. J. Biotechnol. 2007, 128, 638-647.
160. Smagur, A.; Boyko, M.M.; Biront, N.V.; Cichoń, T.; Szala, S. Chimeric protein ABRaA- VEGF121 is cytotoxic towards VEGFR-2-expressing PAE cells and inhibits B16-F10 melanoma growth. Acta Biochim. Pol. 2009, 56, 115-124.
161. Cook, J.P.; Savage, P.M.V.; Lord, J.M.; Roberts, L.M. Biologically active interleukin 2-ricin Achain fusion proteins may require intracellular proteolytic cleavage to exhibit a cytotoxic effect. Bioconjug. Chem. 1993, 4, 440-447.
162. Cereghino, J.L.; Cregg, J.M. Heterologous protein expression in the methylotrophic yeast Pichia pastoris. FEMS Microbiol. Rev. 2000, 24, 45-66.
163. Rajamohan, F.; Doumbia, S.O.; Engstrom, C.R.; Pendergras, S.L.; Maher, D.L.; Uckun, F.M. Expression of biologically active recombinant pokeweed antiviral protein in methylotrophic yeast Pichia pastoris. Protein Expr. Purif. 2000, 18, 193-201.
164. Woo, J.H.; Liu, Y.; Mathias, A.; Stavrou, S.; Wang, Z.; Thompson, J.; Neville, D.M., Jr. Gene optimization is necessary to express a bivalent anti-human anti-T cell immunotoxin in Pichia pastoris. Protein Expr. Purif. 2002, 25, 270-282
165. Della Cristina, P.; Lombardi, A.; Ippoliti, R.; Flavell, D.J.; Flavell, S.U.; Cerotti, A.; Colombatti, M.; Fabbrini, M.S. Systematic comparison between single-chain fusion toxin contructs containing saporin or PEA produced in different expression systems. 2010, in preparation.
166. Holmes, M.A.; Foote, J. Structural consequences of humanizing an antibody. J. Immunol. 1997, 158, 2192-2201.
167. Presta, L.G. Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv. Drug Deliv. Rev. 2006, 58, 640-656.
168. Sharkey, R.M.; Goldenberg, D.M. Use of antibodies and immunoconjugates for the therapy ofmore accessible cancers. Adv. Drug Deliv. Rev. 2008, 60, 1407-1420.
169. Kreitman, R.J.; Wilson, W.H.; White, J.D.; Stetler-Stevenson, M.; Jaffe, E.S.; Giardina, S.; Waldmann, T.A.; Pastan, I. Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2)in patients with hematologic malignancies. J. Clin. Oncol. 2000, 18, 1622-1636.
170. Hassan, R.; Bullock, S.; Premkumar, A.; Kreitman, R.J.; Kindler, H.; Willingham, M.C.; Pastan, I. Phase I study of SS1P a recombinant anti-mesothelin immunotoxin given as a bolus IV infusion to patients with mesothelin-expressing mesothelioma, ovarian and pancreatic cancers. Clin. Canc. Res. 2007, 13, 5144-5149.
171. Molineux, G. Pegylation:engineering improved biopharmaceuticals for oncology. Pharmacotherapy 2003, 23, S3-S8.
172. Onda, M.; Nagata, S.; FitzGerald, D.J.; Beers, R.; Fisher, R.J.; Vincent, J.J.; Lee, B.; Nakamura, M.; Hwang, J.; Kreitman, R.J.; Hassan, R.; Pastan, I. 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. 2006, 177, 8822-8834.
173. Onda, M.; Beers, R.; Xiang, L.; Nagata, S.; Wang, Q.; Pastan, I. An immunotoxin with greatlyreduced immunogenicity by identification and removal of B cell epitopes. Proc. Natl. Acad. Sci. USA 2008, 105, 11311-11316.
174. Chan, S.H.; Shaw, P.C.; Mulot, S.F.; Xu, L.H.; Chan, W.L.; Tam, S.C.; Wong, K.B. Engineeringof a mini-trichosanthin that has lower antigenicity by deleting its C-terminal amino acid residues. Biochem. Biophys. Res. Commun. 2000, 270, 279-285.
175. Bolognesi, A.; Polito, L.; Olivieri, F.; Valbonesi, P.; Barbieri, L.; Battelli, M.G.; Carusi, M.V.; Benvenuto, E.; Del Vecchio Bianco, F.; Di Maro, A.; Parente, A.; Di Loreto, M.; Stirpe, F. Newribosome-inactiv ating protein swith poly nucleotide: Adenosine glycoside aseandanti viralactivities From Basella Rubra L. and Bougainvillea Spectabilis Willd. Planta 1997, 203, 422-429.
176. Cizeau, J.; Grenkow, D.M.; Brown, J.G.; Entwistle, J.; McDonald, G.C. 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. 2009, 32, 574-584.
177. MacDonald, G.C.; Rasamoelisolo, M.; Entwistle, J.; Cizeau, J.; Bosc, D.; Cuthbert, W.; Kowalski, M.; Spearman, M.; Glover, N. A phase I clinical study of VB4-845: Weeklyintratumoral administration of an anti-EpCAM recombinant fusion protein in patients withsquamous cell carcinoma of the head and neck. Drug. Des. Devel. Ther. 2009, 6, 105-14.
178. MacDonald, G.C.; Rasamoelisolo, M.; Entwistle, J.; Cuthbert, W.; Kowalski, M.; Spearman, M.; Glover, N. 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. 2009, 26, 257-264.
179. Baluna, R.; Rizo, J.; Gordon, B.E.; Ghetie, V.; Vitetta, E.S. Evidence for a structural motif intoxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome. Proc. Natl. Acad. Sci. USA. 1999, 96, 3957-3962.
180. Baluna, R.; Coleman, E.; Jones, C.; Ghetie, V.; Vitetta, E.S. The effect of a monoclonal antibodycoupled to ricin A chain-derived peptides on endothelial cells in vitro: Insights into toxin mediated vascular damage. Exp. Cell Res. 2000, 258, 417-424.
181. Vitetta, E.S. Immunotoxins and vascular leak syndrome. Canc. J. 2000, 6, 218-224.
182. Coulson, B.S.; Londrigan, S.L.; Lee, D.J. Rotavirus contains integrin ligand sequences and a disintegrin-like domain that are implicated in virus entry into cells. Proc. Natl. Acad. Sci. USA 1997, 94, 5389-5394.
183. Smallshaw, J.E.; Ghetie, V.; Rizo, J.; Fulmer, J.R.; Trahan, L.L.; Ghetie, M.A.; Vitetta, E.S. Genetic engineering of animmun otoxin to eliminatee pulmonary vascular leakinmice. Nat. Biotechnol. 2003, 21, 387-391.
184. Messmann, R.A.; Vitetta, E.S.; Headlee, D.; Senderowicz, A.M.; Figg, W.D.; Schindler, J.; Michiel, D.F.; Creekmore, S.; Steinberg, S.M.; Kohler, D.; Jaffe, E.S.; Stetler-Stevenson, M.; Chen, H.; Ghetie, V.; Sausville, E.A. A phase I study of combination therapy with immunotoxinsIgG-HD37-deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients withrefractory CD19(+), CD22(+) B cell lymphoma. Clin. Canc. Res. 2000, 6, 1302-1313.
185. Kuroda, K.; Liu, H.; Kim, S.; Guo, M.; Navarro, V.; Bander, N.H. Saporin toxin-conjugatedmonoclonal antibody targeting prostate-specific membrane antigen has potent anticancer activity. Prostate 2010, 70, 1286-1294.
186. Yip, W.L.; Weyergang, A.; Berg, K.; Tønnesen, H.H.; Selbo, P.K. Targeted delivery and enhancedcytotoxicity of cetuximab-saporin by photochemical internalization in EGFR-positive cancer cells. Mol Pharm. 2007, 4, 241-245.
187. Fuchs, H.; Bachran, D.; Panjideh, H.; Schellmann, N.; Weng, A.; Melzig, M.F.; Sutherland, M.; Bachran, C. Saponins as tools for improved targeted tumor therapies. Curr. Drug Targets 2009, 10, 140-151.
188. Weng, A.; Bachran, C.; Fuchs, H.; Krause, E.; Stephanowitz, H.; Melzig, M.F. Enhancement ofsaporin cytotoxicity by Gypsophila saponins more than stimulation of endocytosis. Chem. Biol. Interact. 2009, 176, 204-211.
189. Bachran, D.; Schneider, S.; Urban, C; Weng, A.; Melzig, M.F.; Hoffman, C.; Kaufman, A.M.; Fuchs, H. 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. Canc. 2010, 127, 1453-1461.
190. Bachran, C.; Dürkop H.; Sutherland, M.; Bachran, D.; Müller, C.; Weng, A.; Melzig, M.F.; Fuchs, H. Inhibition of tumor growth by targeted toxins in mice is dramatically improved by saponinum album in a synergistic way. J. Immunother. 2009, 32, 713-725.
191. Ferrari, M. Frontiers in cancer nanomedicine: directing mass transport through biologicalbarriers. Trends Biotechnol. 2010, 28, 181-188.
192. Hoganson, D.K.; Chandler, L.A.; Fleurbaaij, G.A.; Ying, W.; Black, M.E.; Doukas, J.; Pierce, G.F.; Baird, A.; Sosnowski, B.A. Targeted delivery of DNA encoding cytotoxic proteins throughhigh-affinity fibroblast growth factor receptors. Hum. Gene Ther. 1998, 9, 2565-2575.
193. Baird, J.A.; Chandler, L.A.; Sosnowski, B.A. Compositions containing nucleic acids and ligands for therapeutic treatment. US Patent 6,503,886, 13 January 2003.
194. Sajja, H.K.; East, M.P.; Mao, H.; Wang, Y.A.; Nie, S.; Yang, L.; Jankun, J.; Hart, R. Developmentofmultifunctionalnanoparticlesfortargeteddrugdeliveryandnoninvasiveimagingoftherapeutic effect. Curr. Drug. Discov. Technol. 2009, 6, 43-51.
195. Bar, H.; Yacoby, I.; Benhar, I. Killingcancercellsbytargeteddrug-carryingphagenanomedicines. BMC Biotechnol. 2008, 8, 37.
196. Zarovni, N.; Vago, R.; Fabbrini, MS. Saporin suicide gene therapy. Meth. Mol. Biol. 2009, 542,261-283.
197. Jankun, J.; Hart, R. Method of delivery of a medicament to a cancer cell using a pathway ofplasminogen activa tor material. US Patent 5,679,350, 21 October 1997.
198. Weber, R.; Feng, X.; Foord, O.; Green, L.; Gudas, J.M.; Keyt, B.; Liu, Y.; Rathanaswami, P. Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof. US Patent 7,628,986, 8 December 2009.