The protein kinase C agonist PEP005 (ingenol 3-angelate) in the treatment of human cancer: A balance between efficacy and toxicity

Toxins

Volumn 2, Issue 1, 2010, Pages 174-194

  Ersvaer, Elisabeth ^a   Kittang, Astrid Olsnes ^a,b   Hampson, Peter ^c   Sand, Kristoffer ^a   Gjertsen, BjØrn Tore ^a,b   Lord, Janet M ^c   Bruserud, Øystein ^a,b  

^a UNIVERSITY OF BERGEN   (Norway)

^b HAUKELAND UNIVERSITY HOSPITAL   (Norway)

^c UNIVERSITY DEPARTMENT OF MEDICINE   (United Kingdom)

Author keywords

Cancer protein kinase C PEP005

Indexed keywords

CHEMOKINE RECEPTOR CCR1; CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CCR3; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR2; CHEMOKINE RECEPTOR CXCR3; CHEMOKINE RECEPTOR CXCR4; INGENOL MEBUTATE; PROTEIN KINASE C; PROTEIN KINASE C DELTA; PROTEIN KINASE C EPSILON; PROTEIN KINASE C ETA; PROTEIN KINASE C THETA; STROMAL CELL DERIVED FACTOR 1; TGN 1412; ISOENZYME;

ACTINIC KERATOSIS; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CHEMOTHERAPY; CELL INFILTRATION; CYTOKINE RELEASE; CYTOTOXICITY TEST; DRUG DOSE SEQUENCE; DRUG EFFICACY; ENDOTHELIUM CELL; EXPERIMENTAL MODEL; GENE OVEREXPRESSION; HUMAN; HUMORAL IMMUNITY; IMMUNOMODULATION; LEUKEMIA; MULTIMODALITY CANCER THERAPY; MULTIPLE ORGAN FAILURE; NECROSIS; NEOPLASM; NEUTROPHIL CHEMOTAXIS; NONHUMAN; PHENOTYPE; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; RISK BENEFIT ANALYSIS; SKIN CANCER; SKIN INFLAMMATION; SOLID TUMOR; SYSTEMIC DISEASE; SYSTEMIC THERAPY; T LYMPHOCYTE ACTIVATION; ANIMAL; CD8+ T LYMPHOCYTE; MELANOMA; METABOLISM;

ANIMALIA; EUPHORBIA; EUPHORBIA PEPLUS;

ANIMALS; CD8-POSITIVE T-LYMPHOCYTES; HUMANS; ISOENZYMES; MELANOMA; NECROSIS; PROTEIN KINASE C-DELTA;

EID: 77958049128     PISSN: None     EISSN: 20726651     Source Type: Journal    
DOI: 10.3390/toxins2010174     Document Type: Review

References (97)

1. Reikvam, H.; Ersvaer, E.; Bruserud, O. Heat shock protein 90 - a potential target in the treatment of human acute myelogenous leukemia. Curr. Cancer Drug Targets 2009, 9, 761-776.
2. Reikvam, H.; Olsnes, A.M.; Gjertsen, B.T.; Ersvær, E.; Bruserud, Ø. Nuclear Factor-κB signaling - a contributor in leukemogenesis and a target for pharmacological intervention in human acute myelogenous leukemia. Curr. Rev. Oncogen. 2009, in press.
3. Ogbourne, S.M.; Hampson, P.; Lord, J.M.; Parsons, P.; De Witte, P.A.; Suhrbier, A. Proceedings of the First International Conference on PEP005. Anticancer Drugs 2007, 18, 357-362.
4. Kedei, N.; Lundberg, D.J.; Toth, A.; Welburn, P.; Garfield, S.H.; Blumberg, P.M. Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res. 2004, 64, 3243-3255.
5. Hug, H.; Sarre, T.F. Protein kinase C isoenzymes: Divergence in signal transduction? Biochem. J. 1993, 291, 329-343.
6. Ohno, S.; Akita, Y.; Konno, Y.; Imajoh, S.; Suzuki, K. A novel phorbol ester receptor/protein kinase, nPKC, distantly related to the protein kinase C family. Cell 1988, 53. 731-741.
7. Mellor, H.; Parker, P.J. The extended protein kinase C superfamily. Biochem. J. 1998, 332, 281-292.
8. Redig, A.J.; Platanias, L.C. Protein kinase C signaling in leukemia. Leuk. Lymphoma 2008, 49, 1255-1262.
9. Selvatici, R.; Falzarano, S.; Mollica, A.; Spisani, S. Signal transduction pathways triggered by selective formylpeptide analogues in human neutrophils. Eur. J. Pharmacol. 2006, 534, 1-11.
10. Le Good, J.A.; Ziegler, W.H.; Parekh, D.B.; Alessi, D.R.; Cohen, P.; Parker, P.J. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science 1998, 281, 2042-2045.
11. Reyland, M.E. Protein kinase Cδ and apoptosis. Biochem. Soc. Transact. 2007, 35, 1001-1004.
12. Varga, A.; Czifra, G.; Tállai, B.; Németh, T.; Kovács, I.; Kovács, L.; Bíró, T. Tumor gradedependent alterations in the protein kinase C isoform pattern in urinary bladder carcinomas. Eur. Urol. 2004, 46, 462-465.
13. Benzil, D.L.; Finkelstein, S.D.; Epstein, M.H.; Finch P.W. Expression pattern of alpha-protein kinase C in human astrocytomas indicates a role in malignant progression. Cancer Res. 1992, 52, 2951-2956.
14. Mandil, R.; Ashkenazi, E.; Blass, M.; Kronfeld, I.; Kazimirsky, G.; Rosenthal, G.; Umansky, F.; Lorenzo, P.S.; Blumberg, P.M.; Brodie, C. Protein kinase Calpha and protein kinase Cdelta play opposite roles in the proliferation and apoptosis of glioma cells. Cancer Res. 2001; 61, 4612-4619.
15. Ainsworth, P.D.; Winstanley, J.H.; Pearson, J.M.; Bishop, H.M.; Garrod, D.R. Protein kinase C alpha expression in normal breast, ductal carcinoma in situ and invasive ductal carcinoma. Eur. J. Cancer 2004, 40, 2269-2273.
16. Kerfoot, C.; Huang, W.; Rotenberg, S.A. Immunohistochemical analysis of advanced human breast carcinomas reveals downregulation of protein kinase C alpha. J. Histochem. Cytochem. 2004, 52, 419-422.
17. Weichert, W.; Gekeler, V.; Denkert, C.; Dietel, M, Hauptmann, S. Protein kinase C isoform expression in ovarian carcinoma correlates with indicators of poor prognosis. Int. J. Oncol. 2003, 23, 633-639.
18. Brenner, W.; Färber, G.; Herget, T.; Wiesner, C.; Hengstler, J.G.; Thüroff, J.W. Protein kinase C eta is associated with progression of renal cell carcinoma (RCC). Anticancer Res. 2003, 23, 4001-4006.
19. Verstovsek, G.; Byrd, A.; Frey, M.R.; Petrelli, N.J.; Black, J.D. Colonocyte differentiation is associated with increased expression and altered distribution of protein kinase C isozymes. Gastroenterology 1998, 115, 75-85.
20. Hidaka, M.; Nakakuma, H.; Kawaguchi, T.; Nagakura, S.; Horikawa, K.; Okuno, Y.; Kagimoto, T.; Takatsuki, K. Altered expression of protein kinase C in adult T-cell leukemia cells. Int. J. Hematol. 1992, 56, 135-141.
21. Doi, S.; Goldstein, D.; Hug, H.; Weinstein, I.B. Expression of multiple isoforms of protein kinase C in normal human colon mucosa and colon tumors and decreased levels of protein kinase C beta and eta mRNAs in the tumors. Mol. Carcinog. 1994, 11, 197-203.
22. Levy, M.F.; Pocsidio, J.; Guillem, J.G.; Forde, K.; LoGerfo, P.; Weinstein, I.B. Decreased levels of protein kinase C enzyme activity and protein kinase C mRNA in primary colon tumors. Dis. Colon. Rectum. 1993, 36, 913-921.
23. Pongracz, J.; Clark, P.; Neoptolemos, J.P.; Lord, J.M. Expression of protein kinase C isoenzymes in colorectal cancer tissue and their differential activation by different bile acids. Int. J. Cancer 1995, 61, 35-39.
24. Cornford, P.; Evans, J.; Dodson, A.; Parsons, K.; Woolfenden, A.; Neoptolemos, J.; Foster, C.S. Protein kinase C isoenzyme patterns characteristically modulated in early prostate cancer. Am. J. Pathol. 1999, 154, 137-144.
25. Gilhooly, E.M.; Morse-Gaudio, M.; Bianchi, L.; Reinhart, L.; Rose, D.P.; Connolly, J.M.; Reed, J.A.; Albino, A.P. Loss of expression of protein kinase C beta is a common phenomenon in human malignant melanoma: A result of transformation or differentiation? Melanoma Res. 2001, 11, 355-369.
26. Koren, R.; Langzam, L.; Paz, A.; Livne, P.M.; Gal, R.; Sampson, S.R. Protein kinase C (PKC) isoenzymes immunohistochemistry in lymph node revealing solution-fixed, paraffin-embedded bladder tumors. Appl. Immunohistochem. Mol. Morphol. 2000, 8, 166-171.
27. Langzam, L.; Koren, R.; Gal, R.; Kugel, V.; Paz, A.; Farkas, A.; Sampson, S.R. Patterns of protein kinase C isoenzyme expression in transitional cell carcinoma of bladder. Relation to degree of malignancy. Am. J. Clin. Pathol. 2001, 116, 377-385.
28. Kuranami, M.; Powell, C.T.; Hug, H.; Zeng, Z.; Cohen, A.M.; Guillem, J.G. Differential expression of protein kinase C isoforms in human colorectal cancers. J. Surg. Res. 1995, 58, 233-239.
29. Hans, C.P.; Weisenburger, D.D.; Greiner, T.C.; Chan, W.C.; Aoun, P.; Cochran, G.T.; Pan, Z.; Smith, L.M.; Lynch, J.C.; Bociek, R.G.; Bierman, P.J.; Vose, J.M.; Armitage, J.O. Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. Mod. Pathol. 2005, 18, 1377-1384.
30. D'Costa, A.M.; Robinson, J.K.; Maududi, T.; Chaturvedi, V.; Nickoloff, B.J.; Denning, M.F. The proapoptotic tumor suppressor protein kinase C-delta is lost in human squamous cell carcinomas. Oncogene 2006, 25, 378-386.
31. Sharif, T.R.; Sharif, M. Overexpression of protein kinase C epsilon in astroglial brain tumor derived cell lines and primary tumor samples. Int. J. Oncol. 1999, 15, 237-243.
32. Pan, Q.; Bao, L.W.; Kleer, C.G.; Sabel, M.S.; Griffith, K.A.; Teknos, T.N.; Merajver, S.D. Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. Cancer Res. 2005, 65, 8366-8371.
33. Knauf, J.A.; Ward, L.S.; Nikiforov, Y.E.; Nikiforova, M.; Puxeddu, E.; Medvedovic, M.; Liron, T.; Mochly-Rosen, D.; Fagin, J.A. Isozyme-specific abnormalities of PKC in thyroid cancer: Evidence for post-transcriptional changes in PKC epsilon. J. Clin. Endocrinol. Metab. 2002, 87, 2150-2159.
34. Beck, J.; Bohnet, B.; Brügger, D.; Bader, P.; Dietl, J.; Scheper, R.J.; Kandolf, R.; Liu, C.; Niethammer, D.; Gekeler, V. Multiple gene expression analysis reveals distinct differences between G2 and G3 stage breast cancers, and correlations of PKC eta with MDR1, MRP and LRP gene expression. Br. J. Cancer 1998, 77, 87-91.
35. Masso-Welch, P.A.; Winston, J.S.; Edge, S.; Darcy, K.M.; Asch, H.; Vaughan, M.M.; Ip, M.M. Altered expression and localization of PKC eta in human breast tumors. Breast Cancer Res. Treat 2001, 68, 211-223.
36. Blay, P.; Astudillo, A.; Buesa, J.M.; Campo, E.; Abad, M.; García-García, J.; Miquel, R.; Marco, V.; Sierra, M.; Losa, R.; Lacave, A.; Braña, A.; Balbín, M.; Freije, J.M. Protein kinase C theta is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias. Clin. Cancer Res. 2004, 10, 4089-4095.
37. Koivunen, J.; Aaltonen, V.; Peltonen, J. Protein kinase C (PKC) family in cancer progression. Cancer letters 2006, 235, 1-10.
38. Bassini, A.; Zauli, G.; Migliaccio, G.; Migliaccio, A.R.; Pascuccio, M.; Pierpaoli, S.; Guidotti, L.; Capitani, S.; Vitale, M. Lineage-restricted expression of protein kinase C isoforms in hematopoiesis. Blood 1999, 93, 1178-1188.
39. Steinberg S.F. Distinctive activation mechanisms and functions for protein kinase Cdelta. Biochem. J. 2004, 384, 449-459.
40. Yamaguchi, T.; Miki, Y.; Yoshida K. Protein kinase C delta activates IkappaB-kinase alpha to induce the p53 tumor suppressor in response to oxidative stress. Cell Signal 2007, 19, 2088-2097.
41. Abbas, T.; White, D.; Hui, L.; Yoshida, K.; Foster, D.A.; Bargonetti, J. Inhibition of human p53 basal transcription by down-regulation of protein kinase Cdelta. J. Biol. Chem. 2004, 279, 9970-9977.
42. Pearn, L.; Fisher, J.; Burnett, A.K.; Darley, R.L. The role of PKC and PDK1 in monocyte lineage specification by Ras. Blood 2007, 109, 4461-4469.
43. Jackson, D.N.; Foster, D.A. The enigmatic protein kinase Cdelta: Complex roles in cell proliferation and survival. FASEB J. 2004, 18, 627-636.
44. Leitges, M.; Mayr, M.; Braun, U.; Mayr, U.; Li, C.; Pfister, G.; Ghaffari-Tabrizi, N.; Baier, G.; Hu, Y.; Xu, Q. Exacerbated vein graft arteriosclerosis in protein kinase Cdelta-null mice. J. Clin. Invest 2001, 108, 1505-1512.
45. Newton, A.C. Regulation of the ABC kinases by phosphorylation: Protein kinase C as a paradigm. Biochem. J. 2003, 370, 361-371.
46. Zhu, T.; Tsuji, T.; Chen, C. Roles of PKC isoforms in the induction of apoptosis elicited by aberant Ras. Oncogene 2009, doi:10.1038/onc.2009.344.
47. Qi, X.; Mochly-Rosen, D. The PKCδ-Abl complex communicates ER stress to the mitochondria - an essential step in subsequent apoptosis. J. Cell Sci. 2007, 121, 804-813.
48. Humphries, M.J.; Limesand, K.H.; Schneider, J.C.; Nakayama, K.I.; Anderson, S.M.; Reyland, M.E. Suppression of apoptosis in the protein kinase Cdelta null mouse in vivo. J. Biol. Chem. 2006, 281, 9728-9737.
49. Miyamoto, A.; Nakayama, K.; Imaki, H.; Hirose, S.; Jiang, Y.; Abe, M.; Tsukiyama, T.; Nagahama, H.; Ohno, S.; Hatakeyama, S.; Nakayama, K.I. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cdelta. Nature 2002, 416, 865-869.
50. Mecklenbräuker, I.; Saijo, K.; Zheng, N.Y.; Leitges, M.; Tarakhovsky, A. Protein kinase Cdelta controls self-antigen-induced B-cell tolerance. Nature 2002, 416, 860-865.
51. Zabarovsky, E.R.; Lerman, M.I.; Minna, J.D. Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 2002, 21, 6915-6935.
52. Zimmerman, G.A.; Prescott, S.M.; McIntyre, T.M. Endothelial cell interactions with granulocytes: Tethering and signaling molecules. Immunol. Today 1992, 13, 93-100.
53. Imhof, B.A.; Dunon D. Leukocyte migration and adhesion. Adv. Immunol. 1995, 58, 345-416.
54. Springer, T.A. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu. Rev. Physiol. 1995, 57, 827-872.
55. Challacombe, J.M.; Suhrbier, A.; Parsons, P.G.; Jones, B.; Hampson, P.; Kavanagh, D.; Rainger, G.E.; Morris, M.; Lord, J.M.; Le, T.T.; Hoang-Le, D.; Ogbourne, S.M. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J. Immunol. 2006, 177, 8123-8132.
56. Hampson, P.; Kavanagh, D.; Smith, E.; Wang, K.; Lord, J.M.; Ed Rainger, G. The anti-tumor agent, ingenol-3-angelate (PEP005), promotes the recruitment of cytotoxic neutrophils by activation of vascular endothelial cells in a PKC-delta dependent manner. Cancer Immunol. Immunother. 2008, 57, 1241-1251.
57. Siller, G.; Gebauer, K.; Welburn, P.; Katsamas, J.; Ogbourne, S.M. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: Results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study. Austral. J. Dermatol. 2009, 50, 16-22.
58. Anderson, L.; Schmieder, G.J.; Werschler, W.P.; Tschen, E.H.; Ling, M.R.; Stough, D.B.; Katsamas, J. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J. Am. Acad. Dermatol. 2009, 60, 934-943.
59. Olsnes, A.M.; Ersvaer, E.; Ryningen, A.; Paulsen, K.; Hampson, P.; Lord, J.M.; Gjertsen, B.T.; Kristoffersen, E.K.; Bruserud, Ø. The protein kinase C agonist PEP005 increases NF-kappaB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukemia cells. Br. J. Haematol. 2009, 145, 761-774.
60. Hampson, P.; Chahal, H.; Khanim, F.; Hayden, R.; Mulder, A.; Assi, L.K.; Bunce, C.M.; Lord, J.M. PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood 2005, 106, 1362-1368.
61. Bruserud, Ø.; Ryningen, A.; Olsnes, A.M.; Stordrange, L.; Øyan, A.M.; Kalland, K.H.; Gjertsen, B.T. Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells. Haematologica 2007, 92, 332-341.
62. Olsnes, A.M.; Hatfield, K.J.; Bruserud, Ø. The chemokine system and its contribution to leukemogenesis and treatment responsiveness in patients with acute myelogenous leukemia. J. BUON. 2009, 14, 131-140.
63. Kittang, A.M.O.; Hatfield, K.J.; Sand, K.E.; Reikvam, H.; Bruserud, Ø. The chemokine network in acute myelogenous leukemia: Molecular mechanisms involved in leukemogenesis and their therapeutic implications. Cur. Microbiol. Immunol. Rev. 2010, in press.
64. Nakagawa, R.; Soh, J.W.; Michie, A.M. Subversion of protein kinase C alpha signaling in hematopoietic progenitor cells results in the generation of a B -cell chronic lymphocytic leukemia-like population in vivo. Cancer Res. 2006, 66, 527-534.
65. Ghoul, A.; Serova, M.; Astorgues-Xerri, L.; Bieche, I.; Bousquet, G.; Varna, M.; Vidaud, M.; Phillips, E.; Weill, S.; Benhadji, K.A.; Lokiec, F.; Cvitkovic, E.; Faivre, S.; Raymond, E. Epithelial-to-mesenchymal transition and resistance to ingenol 3-angelate, a novel protein kinase C modulator, in colon cancer cells. Cancer Res. 2009, 69, 4260-4269.
66. Gillespie, S.K.; Zhang, X.D.; Hersey, P. Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells. Mol. Cancer Ther. 2004, 3, 1651-1658.
67. Cozzi, S.J.; Parsons, P.G.; Ogbourne, S.M.; Pedley, J.; Boyle, G.M. Induction of senescence in diterpene ester-treated melanoma cells via protein kinase C-dependent hyperactivation of the mitogen-activated protein kinase pathway. Cancer Res. 2006, 66, 10083-10091.
68. Benhadji, K.A.; Serova, M.; Ghoul, A.; Cvitkovic, E.; Le Tourneau, C.; Ogbourne, S.M.; Lokiec, F.; Calvo, F.; Hammel, P.; Faivre, S.; Raymond, E. Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells. Br. J. Cancer 2008, 99, 1808-1815.
69. Serova, M.; Ghoul, A.; Benhadji, K.A.; Faivre, S.; Le Tourneau, C.; Cvitkovic, E.; Lokiec, F.; Lord, J.; Ogbourne, S.M.; Calvo, F.; Raymond, E. Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol. Cancer Ther. 2008, 7, 915-922.
70. Ogbourne, S.M.; Suhrbier, A.; Jones, B.; Cozzi, S.J.; Boyle, G.M.; Morris, M.; McAlpine, D.; Johns, J.; Scott, T.M.; Sutherland, K.P.; Gardner, J.M.; Le, T.T.; Lenarczyk, A.; Aylward, J.H.; Parsons, P.G. Antitumor activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 2004, 64, 2833-2839.
71. Ersvaer, E.; Hampson, P.; Wendelbo, Ø.; Lord, J.M.; Gjertsen, B.T.; Bruserud, Ø. Circulating T cells in patients with untreated acute myelogenous leukemia are heterogeneous and can be activated through the CD3/TCR complex. Hematology 2007, 12, 199-207.
72. Ersvaer, E.; Hampson, P.; Hatfield, K.; Ulvestad, E.; Wendelbo, Ø.; Lord, J.M.; Gjertsen, B.T.; Bruserud, Ø. T cells remaining after intensive chemotherapy for acute myelogenous leukemia show a broad cytokine release profile including high levels of interferon-gamma that can be further increased by a novel protein kinase C agonist PEP005. Cancer Immunol. Immunother. 2007, 56, 913-925.
73. Le, T.T.; Gardner, J.; Hoang-Le, D.; Schmidt, C.W.; MacDonald, K.P.; Lambley, E.; Schroder, W.A.; Ogbourne, S.M.; Suhrbier, A. Immunostimulatory cancer chemotherapy using local ingenol-3-angelate and synergy with immunotherapies. Vaccine 2009, 27, 3053-3062.
74. Shin, S.Y.; Kim, C.G.; Ko, J.; Min, D.S.; Chang, J.S.; Ohba, M.; Kuroki, T.; Choi, Y.B.; Kim, Y.H.; Na, D.S.; Kim, J.W.; Lee, Y.H. Transcriptional and post-transcriptional regulation of the PKC delta gene by etoposide in L1210 murine leukemia cells: Implication of PKC delta autoregulation. J. Mol. Biol. 2004, 340, 681-693.
75. Kaur, S.; Parmar, S.; Smith, J.; Katsoulidis, E.; Li, Y.; Sassano, A.; Majchrzak, B.; Uddin, S.; Tallman, M.S.; Fish, E.N.; Platanias, L.C. Role of protein kinase C-delta (PKC-delta) in the generation of the effects of IFN-alpha in chronic myelogenous leukemia cells. Exp. Hematol. 2005, 33, 550-557.
76. Wood, A.J.; Darbyshire, J. Injury to research volunteers--the clinical-research nightmare. N. Engl. J. Med. 2006, 354, 1869-1871.
77. Farzaneh, L.; Kasahara, N.; Farzaneh, F. The strange case of TGN1412. Cancer Immunol. Immunother. 2007, 56, 129-134.
78. Dayan, C.M.; Wraith, D.C. Preparing for first-in-man studies: The challenges for translational immunology post-TGN1412. Clin. Exp. Immunol. 2008, 151, 231-234.
79. Kenter, M.J.; Cohen, A.F. Establishing risk of human experimentation with drugs: Lessons from TGN1412. Lancet 2006, 368, 1387-1391.
80. Winkler, U.; Jensen, M.; Manzke, O.; Schulz, H.; Diehl, V.; Engert, A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999, 94, 2217-2224.
81. Maghazachi, A. Role of chemokines for natural killer cells. Curr. Topics Microbiol. Immunol. 2010, in press.
82. Carter, P.J.; Senter P.D. Antibody-drug conjugates for cancer therapy. Cancer J. 2008, 14, 154-169.
83. Stasi, R. Gemtuzumab ozogamicin: An anti-CD33 immunoconjugate for the treatment of acute myeloid leukemia. Expert Opin. Biol. Ther. 2008, 8, 527-540.
84. Wong, J.Y. Systemic targeted radionuclide therapy: potential new areas. Int. J. Radiat. Oncol. Biol. Phys. 2006, 66, 74-82.
85. Postema, M.; Gilja, O.H. Ultrasound-directed drug delivery. Curr. Pharm. Biotechnol. 2007, 8, 355-361.
86. Berg, K.; Folini, M.; Prasmickaite, L.; Selbo, P.K.; Bonsted, A.; Engesaeter, B.Ø.; Zaffaroni, N.; Weyergang, A.; Dietze, A.; Maelandsmo, G.M.; Wagner, E.; Norum, O.J.; Høgset, A. Photochemical internalization: A new tool for drug delivery. Curr. Pharm. Biotechnol. 2007, 8, 362-372.
87. Bruserud, Ø.; Foss, B.; Petersen H. Hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders: Studies of granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and Flt-3 ligand (Flt3L). Eur. Cytokine Netw. 2001, 12, 231-238.
88. Ersvaer, E.; Olsnes, A.M.; Bruserud, Ø. The immunological dilemma: Cellular innate and adaptive immune response versus human acute myeloid leukemia. Open Hematol Reviews 2007, 1, 1-14.
89. Dimberg, A. Chemokines in angiogenesis. Curr. Topics Microbiol. Immunol. 2010, in press.
90. Bruserud, Ø. The chemokine system in experimental and clinical hematology. Curr. Topics Microbiol. Immunol. 2010, in press.
91. Bonecchi, R.; Savino, B.; Borroni, E.M.; Mantovani, A.; Locati, M. Chemokine decoy receptors: Structure-function and biological properties. Curr. Topics Microbiol. Immunol. 2010, in press.
92. Løffler, J.; Mezger, M.; Ok, M.; Oliver Morton, C.; Einsele, H. Genetic polymorphisms in the cytokine and chemokine system - their possible importance in allogeneic stem cell transplantation. Curr. Topics Microbiol. Immunol. 2010, in press.
93. Kittan, N.A.; Hildebrandt, G.C. The chemokine system, a possible therapeutic target in acute graft versus host disease. Curr. Topics Microbiol. Immunol. 2010, in press.
94. Reikvam, H.; Hatfield, K.J.; Øyan, A.; Kalland, K.H.; Kittang, A.O.; Bruserud Ø. Primary human acute myelogenous leukemia cells release matrix metalloproteases and their inhibitors: Release profile and pharmacological modulation. Eur. J. Haematol. 2010, in press.
95. Engelhardt, B.G.; Crowe, J.E. Homing in acute graft-versus-host disease: Tissue-specific T regulatory and Th17 cells. Curr. Topics Microbiol. Immunol. 2010, in press.
96. Sandset, P.M. The immunobiology of heparin-induced thrombocytopenia. Curr. Topics Microbiol. Immunol. 2010, in press.
97. Calandra, G. CXCR4 in clinical hematology. Curr. Topics Microbiol. Immunol. 2010, in press