Angiogenesis is a fundamental element of the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the cancerous cells. Activation, migration, proliferation and differentiation of endothelial cells into mature blood vessels is driven by several cytokines and growth factors, known to be dysregulated in hematological malignancies. Thus, therapeutic interventions designed to eradicate the malignant clone should incorporate modulation of the angiogenic cascade. Antiangiogenic agents which target different components of the neovascularization process are being investigated in various solid tumors known to have increased vascularity. The role of angiogenesis in hematological malignancies, the rationale for the use of angiosuppressive therapy for these entities, and the status of novel antiangiogenic agents in clinical trials are discussed.

Keywords:
Angiogenesis, Leukemia, Vascular endothelial growth factor
1.
Folkman J: Tumor angiogenesis: Therapeutic complications. N Engl J Med 1971;285:1182–1186.
2.
Folkman J: Angiogenesis in cancer, vascular, rheumatoid, and other disease. Nat Med 1995;1:27–31.
3.
Folkman J: Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 1995;333:1757–1763.
4.
Boehm T, Folkman J, Browder T, O’Reilly MS: Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 1997;390:404–407.
5.
Cheresh DA: Death to a blood vessel, death to a tumor. Nat Med 1998;4:395–396.
6.
Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E: Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999;103:159–165.
7.
Grant SW, Kyshtoobayeva AS, Kurosaki T, Jakowatz J, Fruehauf JP: Mutant p53 correlates with reduced expression of thrombospondin-1, increased angiogenesis, and metastatic progression in melanoma. Cancer Detect Prev 1998;22:185–194.
8.
Holmgren L, Jackson G, Arbiser J: p53 induces angiogenesis-restricted dormancy in a mouse fibrosarcoma. Oncogene 1998;17:819–824.
9.
Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–364.
10.
Mangi MH, Newland AC: Angiogenesis and angiogenic mediators in haematological malignancies. Br J Haematol 2000;111:43–51.
11.
Liekens S, De Clercq E, Neyts J: Angiogenesis: Regulators and clinical applications. Biochem Pharmacol 2001;61:253–270.
12.
Abedi H, Zachary I: Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem 1997;272:15442–15451.
13.
Mignatti P, Rifkin DB: Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein 1996;49:117–137.
14.
Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD: Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996;87:1171–1180.
15.
Holash J, Wiegand SJ, Yancopoulos GD: New model of tumor angiogenesis: Dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 1999;18:5356–5362.
16.
Breier G, Albrecht U, Sterrer S, Risau W: Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 1992;114:521–532.
17.
Singer AJ, Clark RAF: Cutaneous wound healing. N Engl J Med 1999;341:738–746.
18.
Mukhopadhyay D, Tsiokas L, Zhou XM, Foster D, Brugge JS, Sukhatme VP: Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 1995;375:577–581.
19.
Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996;380:439–442.
20.
Vincenti V, Cassano C, Rocchi M, Persico G: Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 1996;93:1493–1495.
21.
Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA: The human gene for vascular endothelial growth factor: Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991;266:11947–11954.
22.
Nicosia RF: What is the role of vascular endothelial growth factor-related molecules in tumor angiogenesis? Am J Pathol 1998;153:11–16.
23.
Becker ME: Factors promoting tumor angiogenesis. Cancer Invest 1999;17:594–623.
24.
Ferrara N, Alitalo K: Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 1999;5:1359–1364.
25.
Brem S: Angiogenesis and cancer control: From concept to therapeutic trial. Cancer Control 1999;6:436–458.
26.
Tennant TR, Schaeffer CW, Stadler WM: Angiogenesis inhibitors. Curr Oncol Rep 2000;2:11–16.
27.
Ryan CJ, Wilding G: Angiogenesis inhibitors. New agents in cancer therapy. Drugs Aging 2000;17:249–255.
28.
Burrows FJ, Thorpe PE: Vascular targeting – A new approach to the therapy of solid tumors. Pharmacol Ther 1994;64:155–174.
29.
Weidner N, Semple JP, Welch WR, Folkman J: Tumor angiogenesis and metastasis – Correlation in invasive breast carcinoma. N Engl J Med 1991;324:1–8.
30.
Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G: Tumor angiogenesis: A new significant and independent prognostic indicator in early stage breast carcinoma. J Natl Cancer Inst 1992;84:1875–1887.
31.
Macchiarini P, Fontanini G, Hardin MJ, Squartini F, Angeletti CA: Relation of neovascularization to metastasis of non-small-cell lung cancer. Lancet 1992;340:144–146.
32.
Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J: Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993;143:401–409.
33.
Vesalainen S, Lipponen P, Talja M, Alhava E, Syrjanen K: Tumor vascularity and basement membrane structure as prognostic factors in T1–2M0 prostatic adenocarcinoma. Anticancer Res 1994;14:709–714.
34.
Tanigawa N, Matsumura M, Amaya H, Kitaoka A, Shimomatsuya T, Lu C, Muraoka R, Tanaka T: Tumor vascularity correlates with the prognosis of patients with esophageal squamous cell carcinoma. Cancer 1997;79:220–225.
35.
Dickinson AJ, Fox SB, Persad J, Hollyer J, Sibley GN, Harris A: Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 1994;74:762–766.
36.
Jaeger TM, Weidner N, Chew K, Moore DH, Kerschmann RL, Waldman FM, Carroll PR: Tumor angiogenesis correlates with lymph node metastasis in invasive bladder cancer. J Urol 1995;154:69–71.
37.
Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM: Expression of vascular endothelial cell growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995;55:3964–3968.
38.
Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T, Horiuchi T, Muraoka R, Iki M: Extent of tumor vascularization correlates with the prognosis and hematogenous metastasis in gastric carcinomas. Cancer Res 1996;56:2671–2676.
39.
Srivastava A, Laidler P, Davies RP, Horgan K, Hughes LE: The prognostic significance of tumor vascularity in intermediate-thickness (0.76–4.0 mm thick) skin melanoma. Am J Pathol 1988;133:419–423.
40.
Fox SB, Harris AL: Markers of tumor angiogenesis: Clinical applications in prognosis and anti-angiogenic therapy. Invest New Drugs 1997;15:15–28.
41.
DeYoung BR, Wick MR, Fitzgibbon JE, Sirgi KE, Swanson PE: CD31: An immunospecific marker for endothelial differentiation in human neoplasms. Appl Immunohistochem 1993;1:97–100.
42.
Van de Rijin M, Rouse RV: CD34: A review. Appl Immunohistochem 1994;2:71–80.
43.
Perez-Atayde A, Sallan S, Tedrow U, Connors S, Allred E, Folkman J: Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol 1997;150:815–821.
44.
Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D, Koller C, Estrov Z, O’Brien S, Keating M, Freireich E, Albitar M: Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000;96:2240–2245.
45.
Cao Y, Veitonmaki N, Keough K, Cheng H, Lee LS, Zurakowski D: Elevated levels of urine angiostatin and plasminogen/plasmin in cancer patients. Int J Mol Med 2000;5:547–551.
46.
Narendran A, Freedman MH: Pro-angiogenic cytokine pathways in acute lymphoblastic leukemia (abstract 1363). Blood 2000;96(suppl 1):316a.
47.
Veiga JP, Sallan SE, Nadler LM, Cardoso AA: Human acute lymphoblastic leukemia promotes angiogenesis in vivo: Pre-clinical models to develop targeted intervention (abstract 484). Blood 2000;96(suppl 1):113a.
48.
Padró T, Ruiz S, Bieker R, Bürger H, Steins M, Kienast J, Büchner T, Berdel WE, Mesters RM: Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 2000;96:2637–2644.
49.
Hussong JW, Rodgers GM, Shami PJ: Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000;95:309–313.
50.
Di Raimondo F, Palumbo GA, Azzaro MP, Giustolisi R: Angiogenesis in acute myeloid leukemia. Blood 2000;96:3656–3657.
51.
Aguayo A, Estey E, Kantarjian H, Mansouri T, Gidel C, Keating M, Giles F, Estrov Z, Barlogie B, Albitar M: Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood 1999;94:3717–3721.
52.
Verstovsek S, Estey E, Giles FJ, Manshuri T, Beran M, Rogers A, Keating M, Kantarjian H, Albitar M: Clinical relevance of vascular endothelial growth factor (VEGF) receptors 1 and 2 in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) (abstract 441). Blood 2000;94(suppl 1):103a.
53.
Lai R, Estey E, Shen Y, Kantarjian H, Gidel C, Beran M, Manshouri T, Quackenbush R, Keating M, Albitar M: Clinical relevance of plasma endostatin levels in patients with acute myeloid leukemia or myelodysplastic syndrome (abstract 455). Blood 2000;96(suppl 1):106a.
54.
Pruneri G, Bertolini F, Soligo D, Carboni N, Cortelezzi A, Ferrucci PF, Buffa R, Lambertenghi-Deliliers G, Pezzella F: Angiogenesis in myelodysplastic syndromes. Br J Cancer 1999;81:1398–1401.
55.
Lundberg LG, Lerner R, Sundelin P, Rogers R, Folkman J, Palmblad J: Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity. Am J Pathol 2000;157:15–19.
56.
Verstovsek S, Kantarjian H, Manshouri T, Keating M, Estey E, Albitar M: Prognostic significance of VEGF protein levels in the bone marrow of patients with chronic myeloid leukemia (abstract 3197). Blood 2000;96(suppl 1):740a.
57.
Lunin S, Kantarjian H, Manshouri T, Verstovsek S, Talpaz M, Faderl S, Cortes J, Albitar M: Clinical relevance of Flk1/KDR (VEGF-R2) and (VEGF-R1) proteins in chronic myelogenous leukemia (CML) (abstract 1510). Blood 2000;96(suppl 1):350a.
58.
Verstovsek S, Kantarjian H, Manshouri T, Keating M, Estey E, Albitar M: Prognostic significance of Tie-1 protein expression in the bone marrow of patients with chronic myeloid leukemia (abstract 1519). Blood 2000;96(suppl 1):352a.
59.
Mesa RA, Hanson CA, Rajkumar SV, Schroeder G, Tefferi A: Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia. Blood 2000;96:3374–3380.
60.
Di Raimondo F, Azzaro MP, Palumbo GA, Bagnato S, Stagno F, Sortino G, Guglielmo P, Giustolisi R: Elevated VEGF serum levels in idiopathic myelofibrosis (abstract 509). Blood 1999;94(suppl 1):116a.
61.
Kini AR, Kay NE, Peterson LC: Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia. Leukemia 2000;14:1414–1418.
62.
Aguayo A, O’Brien S, Keating M, Manshouri T, Gidel C, Barlogie B, Beran M, Koller C, Kantarjian H, Albitar M: Clinical relevance of intracellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia. Blood 2000;96:768–770.
63.
Molica S, Vitelli G, Levato D, Gandolfo GM, Liso V: Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukemia. Br J Haematol 1999;107:605–610.
64.
Chen H, Treweeke AT, West DC, Till KJ, Cawley JC, Zuzel M, Toh CH: In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells. Blood 2000;96:3181–3187.
65.
Duensing S, Atzpodien J: Increased intracellular and plasma levels of basic fibroblast growth factor in B-cell chronic lymphocytic leukemia. Blood 1995;85:1978–1980.
66.
Shehata MM, Schwarzmeier JD, Hilgarth M, Hubmann R, Berger R, Lechner K: Implication of transforming growth factor beta in bone marrow fibrosis and myelosuppression in hairy cell leukemia (abstract 1566). Blood 2000;96(suppl 1):363a.
67.
Gruber G, Schwarzmeier JD, Shehata M, Hilgarth M, Berger R: Basic fibroblast growth factor is expressed by CD19/CD11c-positive cells in hairy cell leukemia. Blood 2000;94:1077–1085.
68.
Rajkumar SV, Fonseca R, Witzig TE, Gertz MA, Greipp PR: Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma. Leukemia 1999;13:469–472.
69.
Ribatti D, Vacca A, Nico B, Quondamatteo F, Ria R, Minischetti M, Marzullo A, Herken R, Roncali L, Dammacco F: Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br J Cancer 1999;79:451–455.
70.
Rajkumar SV, Leong T, Roche PC, Fonseca R, Dispenzieri A, Lacy MQ, Lust JA, Witzig TE, Kyle RA, Gertz MA, Greipp PR: Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 2000;6:3111–3116.
71.
Vacca A, Di Loreto M, Ribatti D, Di Stefano R, Gadaleta-Caldarola G, Iodice G, Caloro D, Dammacco F: Bone marrow of patients with active multiple myeloma: Angiogenesis and plasma cell adhesion molecules LFA-1, VLA-4, LAM-1, and CD44. Am J Hematol 1995;50:9–14.
72.
Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R, Albini A, Bussolino F, Dammacco F: Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of multiple myeloma. Blood 1999;93:3064–3073.
73.
Di Raimondo F, Azzaro MP, Palumbo G, Bagnato S, Giustolisi G, Floridia P, Sortino G, Giustolisi R: Angiogenic factors in multiple myeloma: Higher levels in bone marrow than in peripheral blood. Haematologica 2000;85:800–805.
74.
Vacca A, Ribatti D, Ruco L, Giacchetta F, Nico B, Quondamatteo F, Ria R, Iurlaro M, Dammacco F: Angiogenesis extent and macrophage density increase simultaneously with pathological progression in B-cell non-Hodgkin’s lymphoma. Br J Cancer 1999;79:965–970.
75.
Salven P, Teerenhovi L, Joensuu H: A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin’s lymphoma. Blood 1997;90:3167–3172.
76.
Foss HD, Araujo I, Demel G, Klotzbach H, Hummel M, Stein H: Expression of vascular endothelial growth factor in lymphomas and Castleman’s disease. J Pathol 1997;183:44–50.
77.
Salven P, Teerenhovi L, Joensuu H: A high pretreatment serum basic-fibroblast growth factor concentration is an independent predictor of poor prognosis in non-Hodgkin’s lymphoma. Blood 1999;94:3334–3339.
78.
Le Bousse-Kerdilès M-C, Chevillard S, Charpentier A, Romquin N, Clay D, Smadja-Joffe F, Praloran V, Dupriez B, Demory J-L, Jasmin C, Martyré M-C: Differential expression of transforming growth factor-β, basic fibroblast growth factor, and their receptors in CD34+ hematopoietic progenitor cells from patients with myelofibrosis and myeloid metaplasia. Blood 1996;88:4534–4546.
79.
Poon RT, Fan S-T, Wong J: Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001;19:1207–1225.
80.
Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J: Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 1994;86:356–361.
81.
Brunner G, Nguyen H, Gabrilove JL, Rifkin DB, Wilson EL: Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells. Blood 1993;81:631–638.
82.
Bikfalvi A, Han ZC: Angiogenic factors are hematopoietic growth factors and vice versa. Leukemia 1994;8:523–529.
83.
Bertolini F, Mancusco P, Gobbi A, Pruneri G: The thin red line: Angiogenesis in normal and malignant hematopoiesis. Exp Hematol 2000;28:993–1000.
84.
Wilson EL, Rifkin DB, Kelly F, Hannocks MJ, Gabrilove JL: Basic fibroblast growth factor stimulates myelopoiesis in long-term human bone marrow cultures. Blood 1991;77:954–960.
85.
Fajardo LF, Allison AC: Tumor necrosis factor α and angiogenesis; in Bicknell R, Lewis CE, Ferrara N (eds): Tumour Angiogenesis. New York, Oxford University Press, 1997, pp 261–271.
86.
Bellamy WT, Richter L, Frutiger Y, Grogan TM: Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 1999;59:728–733.
87.
Vacca A, Ribatti D, Iurlaro M, Albini A, Minischetti M, Bussolino F, Pellegrino A, Ria R, Rusnati M, Presta M, Vincenti V, Persico MG, Dammacco F: Human lymphoblastoid cells produce extracellular matrix-degrading enzymes and induce endothelial cell proliferation, migration, morphogenesis, and angiogenesis. Int J Clin Lab Res 1998;28:55–68.
88.
Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH: Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994;269:26988–26995.
89.
Fielder W, Graeven U, Ergun S, Verago S, Kilic N, Stockschlader M, Hossfeld DK: Vascular endothelial growth factor and its receptors in hematopoietic malignancies. Blood 1997;89:1870–1875.
90.
Fielder W, Graeven U, Ergun S, Verago S, Kilic N, Stockschlader M, Hossfeld DK: Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Am J Pathol 1997;150:1870–1875.
91.
Allouche M, Bayard F, Clamens S, Fillola G, Sie P, Almaric F: Expression of basic fibroblast growth factor (b-FGF) and FGF-receptors in human leukemia cells. Leukemia 1995;9:77–86.
92.
Konig A, Menzel T, Lynen S, Wrazel L, Rosen A, Al-Katib A, Raveche E, Gabrilove JL: Basic fibroblast growth factor (bFGF) upregulates the expression of bcl-2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis. Leukemia 1997;11:258–265.
93.
Menzel T, Rahman Z, Calleja E, White K, Wilson EL, Wieder R, Gabrilove J: Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine. Blood 1996;87:1056–1063.
94.
Munshi N, Wilson CS, Penn J, Epstein J, Singhal S, Hough A, Sanderson R, Desikan R, Siegel D, Mehta J, Barlogie B: Angiogenesis in newly diagnosed multiple myeloma: Poor prognosis with increased microvessel density in bone marrow biopsies (abstract). Blood 1998;92(suppl 1):98a.
95.
Branemark P-I: Bone marrow microvascular. Structure and Function. Adv Microcirc 1968;1:1–65.
96.
Bruyn PPH, Breen PC, Thomas TB: The microcirculation of the bone marrow. Anat Rec 1970;168:55–68.
97.
Abboud C, Lichtman M: Structure of the marrow; in Beutler E, Lichtman MA, Coller BS, Kipps TJ (eds): Hematology, ed 5. New York, McGraw-Hill, 1995, p 25.
98.
Wagner RC: Endothelial cell embryology and growth. Adv Microcirc 1980;9:45.
99.
Andreoni C, Moreau I, Rigal D: Long-term culture of human bone marrow. I. Characterization of adherent cells in flow cytometry. Exp Hematol 1990;18:431–437.
100.
Wilkens BS, Jones DB: Vascular networks within the stroma of human long-term bone marrow cultures. Lab Pathol 1995;177:295–301.
101.
Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC: Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995;376:62–66.
102.
Sensebe L, Deschaseaux M, Li J, Herve P, Charbord P: The broad spectrum of cytokine gene expression by myoid cells from the human marrow microenvironment. Stem Cells 1997;15:133–143.
103.
Thornton DE, Theil K, Payson R, Balcerzak SP, Chiu IM: Characterization of the 5q- breakpoint in an acute nonlymphocytic leukemia patient using pulsed-field gel electrophoresis. Am J Med Genet 1991;41:557–565.
104.
Taichman RS, Reilly MJ, Emerson SG: Human osteoblasts support human hematopoietic progenitor cells in in vitro bone marrow cultures. Blood 1996;88:518–524.
105.
Veiga JP, Kennan TD, Barata JT, Sallan SE, Nadler LM, Cardoso AA: Peroxisome proliferator-activated receptor-γ (PPAR-γ) expression by bone marrow endothelium reveals a potential target for therapeutic intervention in acute lymphoblastic leukemia (abstract 2785). Blood 1999;94(suppl 1):627a.
106.
Veiga JP, Sallan SE, Nadler LM, Cardoso AA: De novo angiogenesis confers a selective advantage to leukemia cells through contact-dependent maintenance of anti-apoptotic gene expression (abstract 2924). Blood 1999;94(suppl 1):658a.
107.
Fielder W, Graeven U, Ergun S, Verago S, Kilic N, Stockschlader M, Hossfeld DK: Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia. Leukemia 1997;11:1234–1237.
108.
Brown LF, Detmar M, Tognazzi K, Abu-Jawdeh G, Iruela-Arispe ML: Uterine smooth muscle cells express functional receptors (flt-1 and KDR) for vascular permeability factor/vascular endothelial growth factor. Lab Invest 1997;76:245–255.
109.
Yang K, Cepko CL: Flk-1, a receptor for vascular endothelial growth factor (VEGF), is expressed by retinal progenitor cells. J Neurosci 1996;16:6089–6099.
110.
Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A: Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 1994;367:576–579.
111.
Bredoux C, Uphoff CC, Drexler HG: Expression of tie receptor tyrosine kinase in human leukemia cell lines. Leuk Res 1997;21:595–601.
112.
Hashiyama M, Iwama A, Ohshiro K, Kurozumi K, Yasunaga K, Shimizu Y, Masuho Y, Matsuda I, Yamaguchi N, Suda T: Predominant expression of a receptor tyrosine kinase, TIE, in hematopoietic stem cells and B cells. Blood 1996;87:93–101.
113.
Batard P, Sansilvestri P, Scheinecker C, Knapp W, Debili N, Vainchenker W, Buhring HJ, Monier MN, Kukk E, Partanen J, Matikainen MT, Alitalo R, Hatzfeld J, Alitalo K: The Tie receptor kinase is expressed by human hematopoietic progenitor cells and by a subset of megakaryocytic cells. Blood 1996;87:2212–2220.
114.
Arap W, Pasqualini R, Ruoslahti E: Chemotherapy targeted to tumor vasculature. Curr Opin Oncol 1998;10:560–565.
115.
Ruoslahti E: Targeting tumor vasculature with homing peptides from phage display. Semin Cancer Biol 2000;10:435–442.
116.
Saiki I, Murata J, Makabe T, Nishi N, Tokura S, Azuma I: Inhibition of tumor angiogenesis by a synthetic cell-adhesive polypeptide containing the Arg-Gly-Asp (RGD) sequence of fibronectin, poly(RGD). Jpn J Cancer Res 1990;81:668–675.
117.
Brooks PC, Clark RA, Cheresh DA: Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 1994;264:569–571.
118.
Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA: Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994;79:1157–1164.
119.
Banks RE, Forbes MA, Kinsey SE, Stanley A, Ingham E, Walters C, Selby PJ: Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: Significance for VEGF measurements and cancer biology. Br J Cancer 1998;77:956–964.
120.
Aguayo A, Estey E, Kantarjian H, Manshouri T, Rogers A, Giles FJ, Albitar M: Longitudinal analysis of angiogenic factors and vascularity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) (abstract 1380). Blood 2000;96(suppl 1):320a.
121.
Flageul B, Wallach D, Cavelier-Balloy B, Bachelez H, Carsuzaa F, Dubertret L: Thalidomide and thrombosis. Ann Dermatol Venereol 2000;127:171–174.
122.
Waltham M, Burnand KG, Collins M, Smith A: Vascular endothelial growth factor and basic fibroblast growth factor are found in resolving venous thrombi. J Vasc Surg 2000;32:988–996.
123.
Jain RK, Schlenger K, Hockel M, Yuan F: Quantitative angiogenesis assays: Progress and problems. Nat Med 1997;3:1203–1208.
124.
O’Reilly MS: The preclinical evaluation of angiogenesis inhibitors. Invest New Drugs 1997;15:5–13.
125.
Miller KD, Sweeney CJ, Slegde GW Jr: Redefining the target: Chemotherapeutics as antiangiogenics. J Clin Oncol 2001;19:1195–1206.
126.
Clements MK, Jones CB, Cumming M, Daoud SS: Antiangiogenic potential of camptothecin and topotecan. Cancer Chemother Pharmacol 1999;44:411–416.
127.
Maragoudakis ME, Peristeris P, Missirlis E, et al: Inhibition of angiogenesis by anthracyclines and titanocene dichloride. Ann NY Acad Sci 1994;732:280–293.
128.
Benbow U, Maitra R, Hamilton J, Brinckerhoff CE: Selective modulation of collagenase 1 gene expression by the chemotherapeutic agent doxorubicin. Clin Cancer Res 1999;5:203–208.
129.
Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN: Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum 1998;41:1258–1265.
130.
Presta M, Rusnati M, Belleri M, Morbidelli L, Ziche M, Ribatti D: Purine analogue 6-methylmercaptopurine riboside inhibits early and late phases of the angiogenesis process. Cancer Res 1999;59:2417–2424.
131.
Vacca A, Iurlaro M, Ribatti D, Minischetti M, Nico B, Ria R, Pellegrino A, Dammacco F: Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 1999;94:4143–4155.
132.
Kakeji Y, Maehara Y, Ikebe M, Teicher BA: Dynamics of tumor oxygenation, CD31 staining and transforming growth factor-beta levels after treatment with radiation or cyclophosphamide in the rat 13762 mammary carcinoma. Int J Radiat Oncol Biol Phys 1997;37:1115–1123.
133.
Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;60:1878–1886.
134.
Fidler I: Regulation of neoplastic angiogenesis. J Natl Cancer Inst Monogr 2001;51:10–14.
135.
Slaton JW, Perrotte P, Inoue K, Dinney CPN, Fidler JJ: Interferon-α-mediated downregulation of angiogenesis-related genes and therapy of bladder cancer are dependent on the optimization of biologic dose and schedule. Clin Cancer Res 1999;5:2726–2734.
136.
Quesada JR, Hersh EM, Manning J, Reuben J, Keating M, Schnipper E, Itri L, Gutterman JU: Treatment of hairy cell leukemia with recombinant alpha-interferon. Blood 1986;68:493–497.
137.
Di Raimondo F, Fichera E, Pia Azzaro M, Stagno F, Palumob GA, Giustolisi R: Low serum levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in IFN-treated chronic myeloid leukemia (CML) patients (abstract 4825). Blood 2000;96 (suppl 1):253b.
138.
Bhatia R, McCarthy JB, Verfaillie CM: Interferon-α restores normal β-1 integrin-mediated inhibition of hematopoietic progenitor proliferation by the marrow microenvironment in chronic myelogenous leukemia. Blood 1996;88:3883–3891.
139.
Sgadari C, Angiolillo AL, Tosato G: Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood 1996;88:3877–3882.
140.
Voest EE, Kenyon BM, O’Reilly MS, Truitt G, D’Amato RJ, Folkman J: Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 1995;87:581–586.
141.
Yao L, Pike SE, Setsuda J, Parekh J, Gupta G, Raffeld M, Jaffe ES, Tosato G: Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12. Blood 2000;96:1900–1905.
142.
D’Amato RJ, Loughnan M, Flynn E, Folkman J: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994;91:4082–4085.
143.
Kenyon BM, Browne F, D’Amato RJ: Effects of thalidomide and related metabolites in a mouse corneal mode of neovascularization. Exp Eye Res 1997;64:971–978.
144.
Sampaio EP, Sarno EN, Galilly R, Chon ZA, Kaplan G: Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991;173:699–703.
145.
Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G: Thalidomide exerts its inhibitory action on tumor necrosis factor by enhancing mRNA degradation. J Exp Med 1993;177:1675–1680.
146.
Turk BE, Jiang H, Liu JO: Binding of thalidomide to 1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor production. Proc Natl Acad Sci USA 1996;93:7552–7556.
147.
Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565–1571.
148.
Barlogie B: Thalidomide (T) in the management of multiple myeloma (MM): The Arkansas experience in >300 patients (Pts) with single agent (SA) and combination therapy (CT) (abstract 28). Proc Am Soc Clin Oncol 2000;19:9a.
149.
Thomas DA: Pilot studies of thalidomide in acute myelogenous leukemia, myelodysplastic syndromes, and myeloproliferative disorders. Semin Hematol 2000;37(suppl 3):26–34.
150.
Estey E, Albitar M, Cortes J, Giles F, Thomas D, Koller C, Beran M, Kantarjian H: Addition of thalidomide (T) to chemotherapy did not increase remission rate in poor prognosis AML/MDS (abstract 1394). Blood 2000;96(suppl 1):323a.
151.
Thomas DA, Kantarjian HM: Current role of thalidomide in cancer treatment. Curr Opin Oncol 2000;12:564–573.
152.
Raza A, Lisak L, Anderews C, Little L, Zorat F, Shetty V, Alvi S, Mundle S, Allampallam K, duRant M, Ekbal M, Muzammil M: Encouraging improvement in cytopenias of patients with myelodysplastic syndromes (MDS) with thalidomide (abstract 111). Proc Am Soc Clin Oncol 2000;19:30a.
153.
Mundle S, Zorat F, Shetty V, Allampallam K, Alvi S, Lisak L, Little L, Dean L, Nascimben F, Ekbal M, duRandt M, Broderick E, Venugopal P, Raza A: Biologic determinants of clinical response to thalidomide in myelodysplasia (abstract 626). Blood 2000;96(suppl 1):146a.
154.
Vajkoczy P, Menger MD, Vollmar B, Schilling L, Schmiedek P, Hirth KP, Ullrich A, Fong TAT: Inhibition of tumor growth, angiogenesis, and microcirculation by the novel flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy. Neoplasia 1999;1:31–41.
155.
Fong TAT, Shawver LK, Li S, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth KP, McMahon G: SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999;59:99–106.
156.
Smolich BD, Yuen HA, West KA, Giles FJ, Albitar M, Cherrington JM: The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood 2001;97:1413–1421.
157.
Rosen L, Mulay M, Mayers A, Kabbinavar F, Rosen P, Cropp G, Hannah A: Phase I dose-escalating trial of SU5416, a novel angiogenesis inhibitor in patients with advanced malignancies (abstract 619). Proc Am Soc Clin Oncol 1999;18:161a.
158.
Fiedler WM, Tinnefeld H, Mende T, Gehling U, Vohwinkel G, Kelsey S, Scigalla P, Hossfeld DK: A phase II study with SU5416 in patients with C-kit positive AML (abstract 1148). Proc Am Soc Clin Oncol 2001;20:288a.
159.
Gordon MS, Talpaz K, Margolin E, Holmgren E, Sledge GW Jr, Benjamin R, Stalter S, Shak S, Adelman D: Phase I trial of recombinant humanized monoclonal anti-vascular endothelial growth factor (anti-VEGF MAB) in patients with metastatic cancer (abstract 1678). Proc Am Soc Clin Oncol 1998;17:210a.
160.
Gately S: The contributions of cyclooxygenase-2 to tumor angiogenesis. Cancer Metastasis Rev 2000;19:19–27.
161.
Dannhardt G, Kiefer W: Cyclooxygenase inhibitors – Current status and future prospects. Eur J Med Chem 2001;36:109–126.
162.
Fosslien E: Molecular pathology of cyclooxygenase-2 in neoplasia. Ann Clin Lab Sci 2000;30:3–21.
163.
Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J: Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 1990;348:555–557.
164.
Kudelka AP, Levy T, Verschraegen CF, Edwards CL, Piamsomboon S, Termrungruanglert W, Freedman RS, Kaplan AL, Kieback DG, Meyers CA, Jaeckle KA, Loyer E, Steger M, Mante R, Mavligit G, Killian A, Tang RA, Gutterman JU, Kavanagh JJ: A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix. Clin Cancer Res 1997;3:1501–1505.
165.
Kudelka AP, Verschraegen CF, Loyer E: Complete remission of metastatic cervical cancer with the angiogenesis inhibitor TNP-470. N Engl J Med 1998;338:991–992.
166.
Dezube BJ, Von Roenn JH, Holden-Wiltse J, Cheung TW, Remick SC, Cooley TP, Moore J, Sommadossi JP, Shriver SL, Suckow CW, Gill PS: Fumagillin analog in the treatment of Kaposi’s sarcoma: A phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team. J Clin Oncol 1998;16:1444–1449.
167.
Sedlakova O, Sedlak J, Hunakova L, Jakubikova J, Duraj J, Sulikova M, Chovancova J, Chorvath B: Angiogenesis inhibitor TNP-470:Cytotoxic effects on human neoplastic cell lines. Neoplasma 1999;46:283–289.
168.
Reuter CWM, Morgan MA, Bergmann L: Targeting the Ras signaling pathway: A rational, mechanism-based treatment for hematologic malignancies. Blood 2000;96:1655–1669.
169.
Feldkamp MM, Lau N, Guha A: Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects. Oncogene 1999;18:7514–7526.
170.
Roboz GJ, Dias S, Lam G, Lane WJ, Soignet SL, Warrell RP Jr, Rafii S: Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood 2000;96:1525–1530.
171.
Lew YS, Brown SL, Griffin RJ, Song CW, Kim JH: Arsenic trioxide causes selective necrosis in solid murine tumors by vascular shutdown. Cancer Res 1999;59:6033–6037.
172.
Scappaticci FA, Smith R, Pathak A, Schloss D, Lum B, Cao Y, Johnson F, Engleman EG, Nolan GP: Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice. Mol Ther 2001;3:186–196.
173.
Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15–R24.
174.
Olson TA, Mohanraj D, Roy S, Ramakrishnan S: Targeting the tumor vasculature: Inhibition of tumor growth by a vascular endothelial growth factor-toxin conjugate. Int J Cancer 1997;73:865–870.
175.
Regulier E, Paul S, Marigliano M, Kintz J, Poitevin Y, Ledoux C, Roecklin D, Cauet G, Calenda V, Homann HE: Adenovirus-mediated delivery of antiangiogenic genes as an antitumor approach. Cancer Gene Ther 2001;8:45–54.
176.
Feldman AL, Libutti SK: Progress in antiangiogenic gene therapy of cancer. Cancer 2000;89:1181–1194.
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2002
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