Apoptin: Therapeutic potential of an early sensor of carcinogenic transformation

Annual Review of Pharmacology and Toxicology

Volumn 48, Issue , 2008, Pages 143-169

  Backendorf, Claude ^a   Visser, Astrid E ^a   De Boer, A G ^b   Zimmerman, Rhyenne ^a   Visser, Mijke ^a   Voskamp, Patrick ^a   Zhang, Ying Hui ^a   Noteborn, Mathieu ^a  

^a LEIDEN UNIVERSITY   (Netherlands)

^b LEIDEN UNIVERSITY   (Netherlands)

Author keywords

Anaphase promoting complex; Apoptin kinase; Apoptosis; Drug targets; Gene therapy; Tumor specific sensor

Indexed keywords

ANTINEOPLASTIC AGENT; APOPTIN; CERAMIDE; NUCLEAR RECEPTOR NUR77; PLASMID DNA; CAPSID PROTEIN; UNCLASSIFIED DRUG; VP3 PROTEIN, CHICKEN ANEMIA VIRUS;

ADENOVIRUS; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BREAST CARCINOMA; CANCER CELL; CANCER SURVIVAL; CARCINOGENESIS; CELL DEATH; CELL KILLING; CYTOPLASM; DNA BINDING; DRUG TARGETING; FOWLPOX VIRUS; HUMAN; LEWIS CARCINOMA; LIVER CELL CARCINOMA; NONHUMAN; ONCOGENE; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN PHOSPHORYLATION; REVIEW; SENSOR; SIMIAN VIRUS 40; SOLID TUMOR; TRANSGENIC MOUSE; TUMOR CELL; TUMOR MODEL; TUMOR REGRESSION; VIRAL GENE DELIVERY SYSTEM; ANIMAL; CELL TRANSFORMATION; DISEASE MODEL; DRUG DELIVERY SYSTEM; DRUG EFFECT; METABOLISM; NEOPLASM;

ANIMALIA; AVES; MUS MUSCULUS;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CAPSID PROTEINS; CELL TRANSFORMATION, NEOPLASTIC; DISEASE MODELS, ANIMAL; DRUG DELIVERY SYSTEMS; HUMANS; NEOPLASMS;

EID: 41149161290     PISSN: 03621642     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.48.121806.154910     Document Type: Review

References (109)

1. Jaroudi S, SenGupta S. 2007. DNA repair in mammalian embryos. Mutat. Res. 635:53-77
2. Dumollard R, Duchen M, Carroll J. 2007. The role of mitochondrial function in the oocyte and embryo. Curr. Top Dev. Biol. 77:21-49
3. Meier P, Finch A, Evan G. 2000. Apoptosis in development. Nature 407:796-801
4. Zhivotovsky B, Orrenius S. 2006. Carcinogenesis and apoptosis: paradigms and paradoxes. Carcinogenesis 27:1939-45
5. Levesque AA, Eastman A. 2007. p53-based cancer therapies: Is defective p53 the Achilles heel of the tumor? Carcinogenesis 28:13-20
6. Walensky LD. 2006. BCL-2 in the crosshairs: tipping the balance of life and death. Cell Death Differ. 13:1339-50
7. White E. 2006. Mechanisms of apoptosis regulation by viral oncogenes in infection and tumorigenesis. Cell Death Differ. 13:1371-77
8. Hersey P, Zhuang L, Zhang XD. 2006. Current strategies in overcoming resistance of cancer cells to apoptosis melanoma as a model. Int. Rev. Cytol. 251:131-58
9. Quintieri L, Fantin M, Vizler C. 2007. Identification of molecular determinants of tumor sensitivity and resistance to anticancer drugs. Adv. Exp. Med. Biol. 593:95-104
10. Macarulla T, Ramos FJ, Capdevila J, Saura C, Tabernero J. 2006. Novel targets for anticancer treatment development in colorectal cancer. Clin. Colorectal Cancer 6:265-72
11. Rodriguez-Nieto S, Zhivotovsky B. 2006. Role of alterations in the apoptotic machinery in sensitivity of cancer cells to treatment. Curr. Pharm. Des. 12:4411-25
12. Vandenabeele P, Vanden Berghe T, Festjens N. 2006. Caspase inhibitors promote alternative cell death pathways. Sci. STKE 2006:pe44
13. Zhang Z, Zhang R. 2005. p53-independent activities of MDM2 and their relevance to cancer therapy. Curr. Cancer Drug Targets 5:9-20
14. Muthumani K, Choo AY, Hwang DS, Ugen KE, Weiner DB. 2004. HIV-1 Vpr: enhancing sensitivity of tumors to apoptosis. Curr. Drug Deliv. 1:335-44
15. Heilman DW, Green MR, Teodoro JG. 2005. The anaphase promoting complex: a critical target for viral proteins and anticancer drugs. Cell Cycle 4:560-63
16. Noteborn MH. 2004. Chicken anemia virus induced apoptosis: underlying molecular mechanisms. Vet. Microbiol. 98:89-94
17. Jeurissen SH, Wagenaar F, Pol JM, van der Eb AJ, Noteborn MH. 1992. Chicken anemia virus causes apoptosis of thymocytes after in vivo infection and of cell lines after in vitro infection. J. Virol. 66:7383-88
18. Noteborn MH, de Boer GF, van Roozelaar DJ, Karreman C, Kranenburg O, et al. 1991. Characterization of cloned chicken anemia virus DNA that contains all elements for the infectious replication cycle. J. Virol. 65:3131-39
19. Noteborn MH, Kranenburg O, Zantema A, Koch G, de Boer GF, van der Eb AJ. 1992. Transcription of the chicken anemia virus (CAV) genome and synthesis of its 52-kDa protein. Gene 118:267-71
20. Phenix KV, Meehan BM, Todd D, McNulty MS. 1994. Transcriptional analysis and genome expression of chicken anaemia virus. J. Gen. Virol. 75(Pt. 4):905-9
21. Koch G, van Roozelaar DJ, Verschueren CA, van der Eb AJ, Noteborn MH. 1995. Immunogenic and protective properties of chicken anaemia virus proteins expressed by baculovirus. Vaccine 13:763-70
22. Peters MA, Jackson DC, Crabb BS, Browning GF. 2002. Chicken anemia virus VP2 is a novel dual specificity protein phosphatase. J. Biol. Chem. 277:39566-73
23. Peters MA, Jackson DC, Crabb BS, Browning GF. 2005. Mutation of chicken anemia virus VP2 differentially affects serine/threonine and tyrosine protein phosphatase activities. J. Gen. Virol. 86:623-30
24. Kamada K, Kuroishi A, Kamahora T, Kabat P, Yamaguchi S, Hino S. 2006. Spliced mRNAs detected during the life cycle of chicken anemia virus. J. Gen. Virol. 87:2227-33
25. Noteborn MH, Todd D, Verschueren CA, de Gauw HW, Curran WL, et al. 1994. A single chicken anemia virus protein induces apoptosis. J. Virol. 68:346-51
26. Noteborn MH. 2005. Apoptin acts as a tumor-specific killer: potentials for an antitumor therapy. Cell Mol. Biol. (Noisy-le-grand) 51:49-60
27. Tavassoli M, Guelen L, Luxon BA, Gaken J. 2005. Apoptin: specific killer of tumor cells? Apoptosis 10:717-24
28. Zhang YH, Leliveld SR, Kooistra K, Molenaar C, Rohn JL, et al. 2003. Recombinant Apoptin multimers kill tumor cells but are nontoxic and epitope-shielded in a normal-cell-specific fashion. Exp. Cell Res. 289:36-46
29. Danen-Van Oorschot AA, Fischer DF, Grimbergen JM, Klein B, et al. 1997. Apoptin induces apoptosis in human transformed and malignant cells but not in normal cells. Proc. Natl. Acad. Sci. USA 94:5843-47
30. Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE. 1988. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J. Cell Biol. 106:761-71
31. Abrahams PJ, Houweling A, van der Eb AJ. 1992. High levels of enhanced reactivation of herpes simplex virus in skin fibroblasts from various hereditary cancer-prone syndromes. Cancer Res. 52:53-57
32. Zhang YH, Abrahams PJ, van der Eb AJ, Noteborn MH. 1999. The viral protein Apoptin induces apoptosis in UV-C-irradiated cells from individuals with various hereditary cancer-prone syndromes. Cancer Res 59:3010-15
33. Zhang YH, Kooistra K, Pietersen A, Rohn JL, Noteborn MH. 2004. Activation of the tumor-specific death effector apoptin and its kinase by an N-terminal determinant of simian virus 40 large T antigen. J. Virol. 78:9965-76
34. Bernards R, Weinberg RA. 2002. A progression puzzle. Nature 418:823
35. Pietersen A, Erkeland SJ, Rutjes SA, Philipsen S, Medema JP, Noteborn MH. 2005. Continuous apoptin expression in transgenic mice does not interfere with lymphocyte development and proliferation. J. Med. Mol. Biol. 2:321-30
36. Leliveld SR, Dame RT, Mommaas MA, Koerten HK, Wyman C, et al. 2003. Apoptin protein multimers form distinct higher-order nucleoprotein complexes with DNA. Nucleic Acids Res. 31:4805-13
37. McGuffin LJ, Bryson K, Jones DT. 2000. The PSIPRED protein structure prediction server. Bioinformatics 16:404-5
38. Leliveld SR, Zhang YH, Rohn JL, Noteborn MH, Abrahams JP. 2003. Apoptin induces tumor-specific apoptosis as a globular multimer. J. Biol. Chem. 278:9042-51
39. Danen-Van Oorschot AA, Zhang YH, Leliveld SR, Rohn JL, Seelen MC, et al. 2003. Importance of nuclear localization of apoptin for tumor-specific induction of apoptosis. J. Biol. Chem. 278:27729-36
40. Guelen L, Paterson H, Gaken J, Meyers M, Farzaneh F, Tavassoli M. 2004. TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells. Oncogene 23:1153-65
41. Liu X, Zeidan YH, Elojeimy S, Holman DH, El-Zawahry AM, et al. 2006. Involvement of sphingolipids in apoptin-induced cell killing. Mol. Ther. 14:627-36
42. Liu X, Elojeimy S, El-Zawahry AM, Holman DH, Bielawska A, et al. 2006. Modulation of ceramide metabolism enhances viral protein apoptin's cytotoxicity in prostate cancer. Mol. Ther. 14:637-46
43. Ogretmen B, Hannun YA. 2004. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 4:604-16
44. Chada S, Ramesh R. 2007. Apoptin studies illuminate intersection between lipidomics and tumor suppressors. Mol. Ther. 15:7-9
45. Rohn JL, Zhang YH, Aalbers RI, Otto N, Den Hertog J, et al. 2002. A tumor-specific kinase activity regulates the viral death protein Apoptin. J. Biol. Chem. 277:50820-27
46. Poon IK, Oro C, Dias MM, Zhang JP, Jans DA. 2005. A tumor cell-specific nuclear targeting signal within chicken anemia virus VP3/apoptin. J. Virol. 79:1339-41
47. Poon IK, Oro C, Dias MM, Zhang J, Jans DA. 2005. Apoptin nuclear accumulation is modulated by a CRM1-recognized nuclear export signal that is active in normal but not in tumor cells. Cancer Res. 65:7059-64
48. Rohn JL, Zhang YH, Leliveld SR, Danen-van Oorschot AA, Henriquez NV, et al. 2005. Relevance of apoptin's integrity for its functional behavior. J. Virol. 79:1337-38
49. Lee YH, Cheng CM, Chang YF, Wang TY, Yuo CY. 2007. Apoptin T108 phosphorylation is not required for its tumor-specific nuclear localization but partially affects its apoptotic activity. Biochem. Biophys. Res. Commun. 354:391-95
50. Liu H, Pope RM. 2003. The role of apoptosis in rheumatoid arthritis. Curr. Opin. Pharmacol. 3:317-22
51. Liu H, Eksarko P, Temkin V, Haines GK 3rd, Perlman H, et al. 2005. Mcl-1 is essential for the survival of synovial fibroblasts in rheumatoid arthritis. J. Immunol. 175:8337-45
52. Michael W, Alisa KE. 2000. Cell cycle implications in the pathogenesis of rheumatoid arthritis. Front Biosci. 5:D594-601
53. Tolboom TC, Zhang YH, Henriquez NV, Nelissen RG, Toes RE, et al. 2006. Fibroblast-like synoviocytes from patients with rheumatoid arthritis are more sensitive to apoptosis induced by the viral protein, Apoptin, than fibroblast-like synoviocytes from trauma patients. Clin. Exp. Rheumatol. 24:142-47
54. Davis LS. 2003. A question of transformation: the synovial fibroblast in rheumatoid arthritis. Am. J. Pathol. 162:1399-402
55. Janssen K, Hofmann TG, Jans DA, Hay RT, Schulze-Osthoff K, Fischer U. 2007. Apoptin is modified by SUMO conjugation and targeted to promyelocytic leukemia protein nuclear bodies. Oncogene 26:1557-66
56. Sun GJ, Tong X, Dong Y, Mei ZZ, Sun ZX. 2002. Identification of a protein interacting with apoptin from human leucocyte cDNA library by using yeast two-hybrid screening. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 34:369-72
57. Schlierf B, Lang S, Kosian T, Werner T, Wegner M. 2005. The high-mobility group transcription factor Sox10 interacts with the N-myc-interacting protein Nmi. J. Mol. Biol. 353:1033-42
58. Danen-van Oorschot AA, Voskamp P, Seelen MC, van Miltenburg MH, Bolk MW, et al. 2004. Human death effector domain-associated factor interacts with the viral apoptosis agonist Apoptin and exerts tumor-preferential cell killing. Cell Death Differ. 11:564-73
59. Stanton SE, McReynolds LJ, Evans T, Schreiber-Agus N. 2006. Yaf2 inhibits caspase 8-mediated apoptosis and regulates cell survival during zebrafish embryogenesis. J. Biol. Chem. 281:28782-93
60. Cheng CM, Huang SP, Chang YF, Chung WY, Yuo CY. 2003. The viral death protein Apoptin interacts with Hippi, the protein interactor of Huntingtin-interacting protein 1. Biochem. Biophys. Res. Commun. 305:359-64
61. Ferner V. 2002. Hip, hip, hippi! Nat. Cell Biol. 4:E30
62. Majumder P, Chattopadhyay B, Mazumder A, Das P, Bhattacharyya NP. 2006. Induction of apoptosis in cells expressing exogenous Hippi, a molecular partner of huntingtin-interacting protein Hip1. Neurobiol. Dis. 22:242-56
63. Maddika S, Booy EP, Johar D, Gibson SB, Ghavami S, Los M. 2005. Cancer-specific toxicity of apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway. J. Cell Sci. 118:4485-93
64. Maddika S, Mendoza FJ, Hauff K, Zamzow CR, Paranjothy T, Los M. 2006. Cancer-selective therapy of the future: apoptin and its mechanism of action. Cancer Biol. Ther. 5:10-19
65. Teodoro JG, Heilman DW, Parker AE, Green MR. 2004. The viral protein Apoptin associates with the anaphase-promoting complex to induce G2/M arrest and apoptosis in the absence of p53. Genes Dev. 18:1952-57
66. Heilman DW, Teodoro JG, Green MR. 2006. Apoptin nucleocytoplasmic shuttling is required for cell type-specific localization, apoptosis, and recruitment of the anaphase-promoting complex/cyclosome to PML bodies. J. Virol. 80:7535-45
67. Almasan A, Ashkenazi A. 2003. Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev. 14:337-48
68. Chaudhari BR, Murphy RF, Agrawal DK. 2006. Following the TRAIL to apoptosis. Immunol. Res. 35:249-62
69. Bhojani MS, Rossu BD, Rehemtulla A. 2003. TRAIL and antitumor responses. Cancer Biol. Ther. 2:S71-78
70. Gopalan B, Shanker M, Chada S, Ramesh R. 2007. MDA-7/IL-24 suppresses human ovarian carcinoma growth in vitro and in vivo. Mol. Cancer 6:11
71. Gopalan B, Litvak A, Sharma S, Mhashilkar AM, Chada S, Ramesh R. 2005. Activation of the Fas-FasL signaling pathway by MDA-7/IL-24 kills human ovarian cancer cells. Cancer Res. 65:3017-24
72. Bocangel D, Zheng M, Mhashilkar A, Liu Y, Ramesh R, et al. 2006. Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2 + breast cancer cells. Cancer Gene Ther. 13:958-68
73. Saito Y, Miyahara R, Gopalan B, Litvak A, Inoue S, et al. 2005. Selective induction of cell cycle arrest and apoptosis in human prostate cancer cells through adenoviral transfer of the melanoma differentiation-associated -7 (mda-7)/interleukin-24 (IL-24) gene. Cancer Gene Ther. 12:238-47
74. Oida Y, Gopalan B, Miyahara R, Inoue S, Branch CD, et al. 2005. Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer. Mol. Cancer Ther. 4:291-304
75. Pataer A, Bocangel D, Chada S, Roth JA, Hunt KK, Swisher SG. 2007. Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl-amino-17-demethoxy analogue. Cancer Gene Ther. 14:12-18
76. Landry MC, Robert A, Lavoie JN. 2006. Alternative cell death pathways: lessons learned from a viral protein. Bull. Cancer 93:921-30
77. Lavoie JN, Champagne C, Gingras MC, Robert A. 2000. Adenovirus E4 open reading frame 4-induced apoptosis involves dysregulation of Src family kinases. J. Cell Biol. 150:1037-56
78. Miron MJ, Gallouzi IE, Lavoie JN, Branton PE. 2004. Nuclear localization of the adenovirus E4orf4 protein is mediated through an arginine-rich motif and correlates with cell death. Oncogene 23:7458-68
79. Gingras MC, Champagne C, Roy M, Lavoie JN. 2002. Cytoplasmic death signal triggered by SRC-mediated phosphorylation of the adenovirus E4orf4 protein. Mol. Cell Biol. 22:41-56
80. Champagne C, Landry MC, Gingras MC, Lavoie JN. 2004. Activation of adenovirus type 2 early region 4 ORF4 cytoplasmic death function by direct binding to Src kinase domain. J. Biol. Chem. 279:25905-15
81. Shtrichman R, Sharf R, Barr H, Dobner T, Kleinberger T. 1999. Induction of apoptosis by adenovirus E4orf4 protein is specific to transformed cells and requires an interaction with protein phosphatase 2A. Proc. Natl. Acad. Sci. USA 96:10080-85
82. Maoz T, Koren R, Ben-Ari I, Kleinberger T. 2005. YND1 interacts with CDC55 and is a novel mediator of E4orf4-induced toxicity. J. Biol. Chem. 280:41270-77
83. Zhao RY, Elder RT. 2005. Viral infections and cell cycle G2/M regulation. Cell Res. 15:143-49
84. Arroyo JD, Hahn WC. 2005. Involvement of PP2A in viral and cellular transformation. Oncogene 24:7746-55
85. Kornitzer D, Sharf R, Kleinberger T. 2001. Adenovirus E4orf4 protein induces PP2A-dependent growth arrest in Saccharomyces cerevisiae and interacts with the anaphase-promoting complex/cyclosome. J. Cell Biol. 154:331-44
86. Svensson M, Hakansson A, Mossberg AK, Linse S, Svanborg C. 2000. Conversion of alpha-lactalbumin to a protein inducing apoptosis. Proc. Natl. Acad. Sci. USA 97:4221-26
87. Fast J, Mossberg AK, Nilsson H, Svanborg C, Akke M, Linse S. 2005. Compact oleic acid m HAMLET. FEBS Lett. 579:6095-100
88. Hallgren O, Gustafsson L, Irjala H, Selivanova G, Orrenius S, Svanborg C. 2006. HAMLET triggers apoptosis but tumor cell death is independent of caspases, Bcl-2 and p53. Apoptosis 11:221-33
89. Goolsby TV, Lombardo FA. 2006. Extravasation of chemotherapeutic agents: prevention and treatment. Semin. Oncol. 33:139-43
90. Olijslagers SJ, Zhang YH, Backendorf C, Noteborn MH. 2007. Additive cytotoxic effect of apoptin and chemotherapeutic agents paclitaxel and etoposide on human tumour cells. Basic Clin. Pharmacol. Toxicol. 100:127-31
91. Zhang YH, Olijslagers S, Backendorf C, Noteborn HM. 2007. Apoptin close-ups: perspectives towards novel therapies. J. Med. Mol. Biol. 3:401-6
92. Pietersen AM, van der Eb MM, Rademaker HJ, van den Wollenberg DJ, Rabelink MJ, et al. 1999. Specific tumor-cell killing with adenovirus vectors containing the apoptin gene. Gene Ther. 6:882-92
93. Pietersen A. 2003. Preclinical studies with apoptin. PhD thesis. The Netherlands: Erasmus Univ. Rotterdam
94. van der Eb MM, Pietersen AM, Speetjens FM, Kuppen PJ, van de Velde CJ, et al. 2002. Gene therapy with apoptin induces regression of xenografted human hepatomas. Cancer Gene Ther. 9:53-61
95. Li X, Jin N, Mi Z, Lian H, Sun L, etal. 2006. Antitumor effects of a recombinant fowl pox virus expressing Apoptin in vivo and in vitro. Int. J. Cancer 119:2948-57
96. Lian H, Jin N, Li X, Mi Z, Zhang J, et al. 2007. Induction of an effective antitumor immune response and tumor regression by combined administration of IL-18 and Apoptin. Cancer Immunol. Immunother. 56:181-92
97. Adair BM. 2000. Immunopathogenesis of chicken anemia virus infection. Dev. Comp. Immunol. 24:247-55
98. Peng DJ, Sun J, Wang YZ, Tian J, Zhang YH, et al. 2007. Inhibition of hepatocarcinoma by systemic delivery of Apoptin gene via the hepatic asialoglycoprotein receptor. Cancer Gene Ther. 14:66-73
99. Olijslagers S. 2003. Gene therapeutic application of the chicken anemia virus derived protein Apoptin. PhD thesis. Germany: Ruprecht-Karl Univ. Heidelberg
100. Yang ZR, Wang HF, Zhao J, Peng YY, Wang J, et al. 2 007. Recent developments in the use of adenoviruses and immunotoxins in cancer gene therapy. Cancer Gene Ther. 14:599-615
101. Rots MG, Elferink MG, Gommans WM, Oosterhuis D, Schalk JA, et al. 2006. An ex vivo human model system to evaluate specificity of replicating and non-replicating gene therapy agents. J. Gene Med. 8:35-41
102. Gommans WM, McLaughlin PM, Schalk JA, Groothuis GM, Haisma HJ, Rots MG. 2007. Highly efficient and carcinoma-specific adenoviral replication restricted by the EGP-2 promoter. J. Control Release 117:1-10
103. de Boer AG, Gaillard PJ. 2007. Drug targeting to the brain. Annu. Rev. Pharmacol. Toxicol. 47:323-55
104. Smith RM, Wu GY. 1999. Hepatocyte-directed gene delivery by receptor-mediated endocytosis. Semin. Liver Dis. 19:83-92
105. Raab G, Klagsbrun M. 1997. Heparin-binding EGF-like growth factor. Biochim. Biophys. Acta 1333:F179-99
106. Mishima K, Higashiyama S, Asai A, Yamaoka K, Nagashima Y, et al. 1998. Heparin-binding epidermal growth factor-like growth factor stimulates mitogenic signaling and is highly expressed in human malignant gliomas. Acta Neuropathol. (Berl.) 96:322-28
107. Downing MT, Brigstock DR, Luquette MH, Crissman-Combs M, Besner GE. 1997. Immunohistochemical localization of heparin-binding epidermal growth factor-like growth factor in normal skin and skin cancers. Histochem. J. 29:735-44
108. Buzzi S, Rubboli D, Buzzi G, Buzzi AM, Morisi C, Pironi F. 2004. CRM197 (nontoxic diphtheria toxin): effects on advanced cancer patients. Cancer Immunol. Immunother. 53:1041-48
109. Gaillard PJ, Brink A, de Boer AG. 2005. Diphtheria toxin receptor-targeted brain drug delivery. Int. Congr. Ser. 1277:185-95