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Thromb Haemost 2001; 86(01): 23-33
DOI: 10.1055/s-0037-1616197
DOI: 10.1055/s-0037-1616197
Research Article
Angiogenesis Research: Guidelines for Translation to Clinical Application
Further Information
Publication History
Publication Date:
12 December 2017 (online)
Summary
Angiogenesis research is being translated to the clinic. Certain guidelines may facilitate this effort. Recruitment of endothelial cells by a tumor is an early event in angiogenesis, a process regulated at genetic and epigenetic levels. The microvascular endothelial cell has become an important second target in cancer therapy. Angiogenesis inhibitors are either “direct” or “indirect” and their optimal dosing depends on a different logic than conventional chemotherapy. Conversely, antiangiogenic scheduling of chemotherapy can by-pass drug resistance. Like all solid tumors, hematologic malignancies are angiogenesis-dependent. Further, angiogenesis is modulated by proteins and cells from the hematopoietic and hemostatic systems. Clinical testing of angiogenesis inhibitors has accentuated the need for surrogate markers of tumor angiogenesis activity. Microvessel density, so valuable as a prognostic indicator of metastatic risk, cannot determine efficacy of an angiogenesis inhibitor. In the future, angiogenesis inhibitors may be added to chemotherapy or to radiotherapy, or to other modalities. Also, combinations of angiogenesis inhibitors may be administered together.
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References
- 1 Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182-6.
- 2 Folkman J. Antiangiogenesis: new concept for therapy of solid tumors. Ann Surg 1972; 175: 408-16.
- 3 Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362: 841-4.
- 4 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: 576-9.
- 5 Lyden D, Young AZ, Zagzag D, Yan W, Gerald W, O’Reilly R, Bader BL, Hynes RO, Zhuang Y, Manova K, Benezra R. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 1999; 401: 670-7.
- 6 Streit M, Riccardi L, Velasco P, Brown LF, Hawighorst T, Bornstein P, Detmar M. Thrombospondin-2: A potent endogenous inhibitor of tumor growth and angiogenesis. Proc Natl Acad Sci USA 1999; 96: 14888-93.
- 7 Folkman J. Tumor angiogenesis. In: Cancer Medicine, 5th Edition. Holland JF, Frei III E, Bast Jr RC, Kufe DW, Pollock RE, Weichselbaum RR. eds. Ontario, Canada: B. C. Decker, Inc.; 2000: 132-52.
- 8 Folkman J. Angiogenesis. In: Harrison’s Textbook of Internal Medicine, 15th Edition. Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL. eds. New York: McGraw-Hill; 2001: 517-30.
- 9 Tumour angiogenesis. Bicknell RJ, Lewis CE, Ferrara N. eds. Cary, North Carolina: Oxford University Press; 1997
- 10 Angiogenesis.. From the molecular to integrative pharmacology. Advances in Experimental Medicine and Biology. Volume 476. Maragoudakis ME. ed. New York: Kluwer Academic/Plenum Publishers; 2000
- 11 Antiangiogenic agents in cancer therapy. Teicher BA. ed. Totawa, New Jersey: Humana Press; 1999
- 12 Folkman J, Hahnfeldt P, Hlatky L. Cancer looking outside the genome. Nature Reviews Molecular Cell Biology 2000; 1: 76-9.
- 13 Rak JW, St Croix BD, Kerbel RS. Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. Anticancer Drugs 1995; 6: 3-18.
- 14 Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent resistance to anticancer therapeutic agents. BioEssays 1991; 1: 31-6.
- 15 Boehm T, Folkman J, Browder T, O’Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 1997; 390: 404-7.
- 16 National Cancer Institute, Cancer Information Service, Building 31, 31 Center Drive, MSC 2580, Bethesda, Maryland, 20892, 301-435-3848 (web address: cancer trials.nci.nih.gov ) 2001.
- 17 Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H-J, Bendict W, Bouck NP. Pigment epithelium-derived factor: A potent inhibitor of angiogenesis. Science 1999; 285: 245-8.
- 18 Kudelka AP. Complete regression of metastatic cervical cancer with the angiogenesis inhibitor TNP-470. N Engl J Med 1998; 338: 991-2.
- 19 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: 1878-86.
- 20 Folkman J, Mulliken JB, Ezekowitz RAB. Antiangiogenic therapy of haemangiomas with interferon A. In: The Clinical Applications of the Interferons. Stuart-Harris R, Penny R. eds. London: Chapman & Hall Medical; 1997: 255-65.
- 21 Singh RK, Gutman M, Bucana CD, Sanchez R, Llansa N, Fidler IJ. Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. Proc Natl Acad Sci USA 1995; 92: 4562-6.
- 22 D’Amato RJ, Lin CM, Flynn E, Folkman J, Hamel E. 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Natl Acad Sci USA 1994; 91: 3964-8.
- 23 Rastinejad F, Polverini P, Bouck NP. Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 1989; 56: 345-55.
- 24 O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315-28.
- 25 O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277-85.
- 26 Bouck N. Tumor angiogenesis: The role of oncogenes and tumor suppressor genes. Cancer Cells 1990; 2: 179-85.
- 27 Bischoff J, Brasel C, Kraling B, Vranovska K. E-selectin is upregulated in proliferating endothelial cells in vitro. Microcirculation 1997; 4: 279-87.
- 28 Ito K, Ye CL, Hibi K, Mitsuoka C, Kannagi R, Kasai Y, Akiyama S, Nakao A. Soluble E-selectin and its ligand sialyl-Lea in human colorectal cancer. Proc Amer Assoc Cancer Res 2001; 42: 612a (abstr.).
- 29 Meta-analysis Group in Cancer.. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: 301-8.
- 30 Gabra H, Cameron DA, Lee LE, Mackay J, Leonard RC. Weekly doxorubicin and continuous infusional 5-fluorouracil for advanced breast cancer. Br J Cancer 1996; 74: 2008-12.
- 31 Hansen RM, Ryan L, Anderson T, Krzywda B, Quebbeman E, Benson 3rd A, Haller DG, Tormey DC. Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst 1996; 88: 668-74.
- 32 Seidman AD, Hudis CA, Albanel J, Tong W, Tepler I, Currie V, Moynahan ME, Theodoulou M, Gollub M, Baselga J, Norton L. Dose-dense therapy with weekly 1-hour paclitaxel infusions in treatment of metastatic breast cancer. J Clin Oncol 1998; 16: 3353-61.
- 33 Abe-Rustum NR, Aghajanian C, Barakat RR, Fennelly D, Shapiro F, Spriggs D. Salvage weekly paclitaxel in recurrent ovarian cancer. Semin Oncol 1997; 24 (Suppl. 15) 62-7.
- 34 Loffler TM, Freund W, Lipke J, Hausamen TU. Schedule- and dose-intensified paclitaxel as weekly 1-hour infusion in pretreated solid tumors: results of a phase I/II trial. Semin Oncol 1996; 23 6 suppl 16 32-4.
- 35 Kakolyris S, Samonis G, Koukourakis M, Vlachonicolis I, Chalkiadakis G, Kalbakis K, Souglakos I, Agelaki S, Toloudis P, Georgoulias V. Treatment of non-small-cell lung cancer with prolonged oral etoposide. Am J Clin Oncol 1998; 21: 505-8.
- 36 Chamberlain MC. Recurrent supratentorial malignant gliomas in children. Long-term salvage therapy with oral etoposide. Arch Neurol 1997; 54: 554-8.
- 37 Neskovic-Konstantinovic ZB, Bosnjak SM, Radulovic SS, Mitrovic LB. Daily oral etoposide in metastatic breast cancer. Anticancer Drugs 1996; 7: 543-7.
- 38 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.
- 39 Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000; 105: 1045-7.
- 40 Belotti D, Vergani V, Drudis T, Borsotti P, Pitelli MR, Viale G, Giavazzi R, Taraboletti G. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 1996; 2: 1843-9.
- 41 Arap W, Pasqualini R, Ruoslahti E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 1998; 279: 377-80.
- 42 Folkman J. Regulation of angiogenesis. Blood 1993; 82 (Suppl. 01) 60.
- 43 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: 356-61.
- 44 Brunner G, Nguyen H, Gabrilove J, Rifkin DB, Wilson EL. Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells. Blood 1993; 81: 631-8.
- 45 Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F, Dammacco F. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 1994; 87: 503-8.
- 46 Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma. New Engl J Med 1991; 324: 1-8.
- 47 Ribatti D, Vacca A, Nico B, Quondamatteo F, Ria R, Minischetti M, Marzullo A, Herken R, Roncali L, Dammacco F. Bone marrow angio-genesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br J Cancer 1999; 79: 451-5.
- 48 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 human multiple myeloma. Blood 1999; 93: 3064-73.
- 49 Vacca A, Ribatti D, Roncali L, Dammacco F. Angiogenesis in B cell lymphoproliferative diseases. Biological and clinical studies. Leuk Lymphoma 1995; 20: 27-38.
- 50 Perez-Atayde AR, Sallan SE, 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: 815-21.
- 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: 3717-21.
- 52 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 Research 2000; 6: 3111-6.
- 53 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: 15-9.
- 54 Abstract volume of the 42nd Annual Meeting of the American Society of Hematology. Blood 2000; 96 (Suppl. 11) 1-933a.
- 55 Palmblad J, Lerner R, Lundberg LG. Vascular density, intracellular VEGF and bFGF positivity as prognostic factors in polycythemia vera and chronic myelocytic leukemia. Blood. 2000 96. abstract 257b.
- 56 Palmblad J. Angiogenesis in hematologic malignancies with focus on multiple myeloma. In press 2001
- 57 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 activity in vitro and antitumor efficacy in leukemia and solid tumors in mice. Mol Ther 2001; 3: 186-96.
- 58 D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Nat Acad Sci USA 1994; 91: 4082-5.
- 59 Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeldis J, Barlogie B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565-71.
- 60 Rajkumar SV, Witzig TE. A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treat Rev 2000; 26: 351-62.
- 61 Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai Y-T, Treon SP, Lin B, Schlossman RL, Richardson P, Muller G, Stirling DI, Anderson KC. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96: 2943-50.
- 62 Rajkumar SV, Fonseca R, Dispenzieri A, Lacy MQ, Lust JA, Witzig TE, Kyle RA, Gertz MA, Greipp PR. Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clin Proc 2000; 75: 897-901.
- 63 Zomas A, Anagnostopoulos N, Dimopoulos MA. Successful treatment of multiple myeloma as a single agent. Bone Marrow Transplant 2000; 25: 1319-20.
- 64 Weber DM, Rankin K, Gavino M, Delasalle K, Aguayo A, Albitar M, Alexanian R. Angiogenesis factors and sensitivity to thalidomide in previously untreated multiple myeloma (MM). Blood. 2000 96: 168a, abstract #724.
- 65 Pini M, Baraldi A, Pietrasanta D, Allione B, Depaoli L, Salvi F, Levis A. Low-dose thalidomide in the treatment of refractory myeloma. Haematologica 2000; 85: 1111-2.
- 66 Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K. Antiangiogenic antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306-11.
- 67 Xin X, Yang S, Kowalski J, Gerritsen ME. Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 1999; 273: 9116-21.
- 68 Roboz GJ, Dias S, Lam G, Lane WJ, Soignet SL, Warrell Jr RP, 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: 1525-30.
- 69 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: 469-72.
- 70 Raje N, Anderson K. Thalidomide – a revival story. N Engl J Med 1999; 341: 1606-9.
- 71 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: 1875-87.
- 72 Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumor angio-genesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993; 143: 401-9.
- 73 Gasparini G, Harris AL. Prognostic significance of tumor vascularity. In: Antiangiogenic Agents in Cancer Therapy. Teicher BA. editor. New Jersey: Humana Press; 1999: 317-39.
- 74 Hlatky L, Hahnfeldt P, Folkman J. Clinical Application of Antiangiogenic Therapy: Microvessel Density, What It Does and Doesn’t Tell Us. 2001 (submitted manuscript).
- 75 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis. J Biol Chem 2000; 275: 1521-4.
- 76 Verheul HMW, Hoekman K, Luykx-de Bakker S, Eekman CA, Folman CC, Broxterman HJ, Pinedo HM. Platelet: Transporter of vascular endothelial growth factor. Clinical Can Res 1997; 3: 2187-90.
- 77 Blei F, Wilson EL, Mignatti P, Rifkin DB. Mechanism of action of angiostatic steroids: suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis. J Cell Physiol 1993; 155: 568-78.
- 78 Plow EF, Collen D. The presence and release of alpha2-antiplasmin from human platelets. Blood 1981; 58: 1069-74.
- 79 Nachman RL, Harpel PC. Platelet alpha2-macroglobulin and alpha1-antitrypsin. J Biol Chem 1976; 251: 4512-21.
- 80 Fukao H, Ueshima S, Okada K, Matsuo O. The role of the pericellular fibrinolytic system in angiogenesis. Jpn J Physiol 1997; 47: 161-71.
- 81 Colman RW, Lin Y, Johnson D, Mousa SA. Inhibition of angiogenesis by peptides derived from kininogen. Blood. 1998 92 (suppl): 174a abstract #701.
- 82 Rhim TY, Park C-S, Kim E, Kim SS. Human prothrombin fragment 1 and 2 inhibit bFGF-induced BCE cell growth. Biochem Biophys Res Commun 1998; 252: 513-6.
- 83 O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 1999; 285: 1926-31.
- 84 O’Reilly MS, Holmgren L, Chen C, Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996; 2: 689-92.
- 85 Cao Y, Ji RW, Davidson D, Schaller J, Marti D, Sohndel S, McCance SG, O’Reilly MS, Llinas M, Folkman J. Kringle domains of angiostatin: characterization of the anti-proliferative activity on endothelial cells. J Biol Chem 1996; 271: 29461-7.
- 86 Colman RW. Role of the light chain of high molecular weight kininogen in adhesion, cell-associated proteolysis and angiogenesis. J Biol Chem 2001; 382: 65-70.
- 87 Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM. Bone marrow origin of endothelial cell progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circulation Res 1999; 85: 221-8.
- 88 Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li TM, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-7.
- 89 Shi Q, Rafii S, Wu MH-D, Wijelath ES, Yu C, Ishida A, Fujita Y, Kothari S, Mohle R, Sauvage LR, Moore MAS, Storb RF, Hammond WP. Evidence for circulating bone marrow-derived endothelial cells. Blood 1998; 92: 362-7.
- 90 Choi K, Kennedy M, Kazarov A, Papdimtriou JC, Keller GA. A common precursor for hematopoietic and endothelial cells. Development 1998; 125: 725-32.
- 91 Hatzopoulos AK, Folkman J, Vasile E, Eiselen GK, Rosenbereg RD. Isolation and characterization of endothelial progenitor cells from mouse embryos. Development 1998; 125: 1457-68.
- 92 Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nature Med 1999; 5: 434-8.
- 93 Isner JM, Asahara T. Angiogenesis and vasculogenesis as therapeutic strategies for post-natal neovascularization. J Clin Invest 1999; 103: 1231-6.
- 94 Ito H, Rovira II, Bloom ML, Takeda K, Ferrans VJ, Quyyumi AA, Finkel T. Endothelial progenitor cells as putative targets for angiostatin. Cancer Res 1999; 59: 5875-7.
- 95 Kocher AA, Schuster Md, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nature Med 2001; 7: 430-6.
- 96 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353-64.
- 97 Kerbel RS, Viloria-Petit A, Okada F, Rak J. Establishing a link between oncogenes and tumor angiogenesis. Molecular Med 1998; 4: 286-95.
- 98 Rak J, Yu JL, Klement G, Kerbel RS. Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J Invest Dermatol Sym Proc 2000; 5: 24-33.
- 99 Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031-7.
- 100 Uehara H, Kim SJ, Karashima T, Zheng L, Fidler IJ. Blockade of PDGF-R signaling by STI571 inhibits angiogenesis and growth of human prostate cancer cells in the bone of nude mice. Proc Amer Assoc Cancer Res 2001; 42: abstract #2192.
- 101 Folkman J. Can mosaic tumor vessels facilitate molecular diagnosis of cancer?. Commentary Proc Natl Acad Sci USA 2001; 98: 398-400.
- 102 Folkman J, Hahnfeldt P, Hlatky L. The logic of antiangiogenic gene therapy. In: The Development of Human Gene Therapy. Friedmann T. ed. New York: Cold Spring Harbor Laboratory Press; 1998: 527-43.