The understanding that tumor growth and metastasis are angiogenesis dependent processes has led to interest in targeting tumor vasculature in anticancer therapy. Furthermore, recent insights into the molecular interactions that orchestrate physiologic and pathologic angiogenesis have resulted in a variety of antiangiogenic strategies. A gene therapy-mediated approach for the delivery of antiangiogenic agents has several advantages, including the potential for sustained expression. However, the choice of angiogenesis inhibitor, method of gene delivery, and target/site for transgene expression are important variables to be considered when designing this approach. Here we review the major alternatives within each of these categories and provide illustrative examples of their use in preclinical models.
CarmelietP.Angiogenesis in Health and Disease. Nat. Med.9, 653–660 (2003).
2.
JainR. K.Molecular Regulation of Vessel Maturation. Nat. Med.9, 685–693 (2003).
3.
PapettiM., HermanI. M.Mechanisms of Normal and Tumor-Derived Angiogenesis. Am. J. Physiol Cell Physiol282, C947–C970 (2002).
4.
YancopoulosG. D., DavisS., GaleN. W., RudgeJ. S., WiegandS. J., HolashJ.Vascular-Specific Growth Factors and Blood Vessel Formation. Nature407, 242–248 (2000).
5.
FolkmanJ.Tumor Angiogenesis: Therapeutic Implications. New England Journal of Medicine285, 1182–1186 (1971).
6.
FolkmanJ.Fundamental Concepts of the Angiogenic Process. Curr. Mol Med.3, 643–651 (2003).
7.
CarmelietP., JainR. K.Angiogenesis in Cancer and Other Diseases. Nature407, 249–257 (2000).
8.
FolkmanJ.Role of Angiogenesis in Tumor Growth and Metastasis. Seminars in Oncology29, 15–18 (2002).
9.
TangD. G., ContiC. J.Endothelial Cell Development, Vasculogenesis, Angiogenesis, and Tumor Neovascularization: An Update. Seminars in Thrombosis and Hemostasis30, 109–117 (2004).
10.
FidlerI. J., EllisL. M.Neoplastic Angiogenesis-Not All Blood Vessels Are Created Equal. New England Journal of Medicine351, 215–216 (2004).
11.
BoehmT., FolkmanJ., BrowderT., O'ReillyM. S.Antiangiogenic Therapy of Experimental Cancer Does Not Induce Acquired Drug Resistance. Nature390, 404–407 (1997).
12.
DalesJ. P., GarciaS., CarpentierS., AndracL., RamuzO., LavautM. N., AllasiaC., BonnierP., Taranger-CharpinC.Prediction of Metastasis Risk (11 Year Follow-Up) Using VEGF-R1, VEGF-R2, Tie-2/Tek and CD105 Expression in Breast Cancer (n=905). British Journal of Cancer90, 1216–1221 (2004).
13.
LiC., GardyR., SeonB. K., DuffS. E., AbdallaS., RenehanA., O'DwyerS. T., HaboubiN., KumarS.Both High Intratumoral Microvessel Density Determined Using CD105 Antibody and Elevated Plasma Levels of CD105 in Colorectal Cancer Patients Correlate With Poor Prognosis. British Journal of Cancer88, 1424–1431 (2003).
14.
HanH., SilvermanJ. F., SantucciT. S., MachereyR. S., d'AmatoT. A., TungM. Y., WeyantR. J., LandreneauR. J.Vascular Endothelial Growth Factor Expression in Stage I Non-Small Cell Lung Cancer Correlates With Neoangiogenesis and a Poor Prognosis. Ann. Surg. Oncol8, 72–79 (2001).
15.
MeitarD., CrawfordS. E., RademakerA. W., CohnS. L.Tumor Angiogenesis Correlates With Metastatic Disease, N-Myc Amplification, and Poor Outcome in Human Neuroblastoma. J Clin. Oncol14, 405–414 (1996).
16.
AbramsonL. P., GrundyP. E., RademakerA. W., HelenowskiI., CornwellM., KatzensteinH. M., ReynoldsM., ArensmanR. M., CrawfordS. E.Increased Microvascular Density Predicts Relapse in Wilms' Tumor. Journal of Pediatric Surgery38, 325–330 (2003).
17.
FerraraN.Role of Vascular Endothelial Growth Factor in Physiologic and Pathologic Angiogenesis: Therapeutic Implications. Seminars in Oncology29, 10–14 (2002).
18.
HicklinD. J., EllisL. M.Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis. Journal of Clinical Oncology23, 1011–1027 (2005).
19.
JainR. K.Tumor Angiogenesis and Accessibility: Role of Vascular Endothelial Growth Factor. Seminars in Oncology29, 3–9 (2002).
20.
KimE. S., SerurA., HuangJ., ManleyC. A., McCruddenK. W., FrischerJ. S., SofferS. Z., RingL., NewT., ZabskiS., RudgeJ. S., HolashJ., YancopoulosG. D., KandelJ. J., YamashiroD. J.Potent VEGF Blockade Causes Regression of Coopted Vessels in a Model of Neuroblastoma. Proc. Natl. Acad. Sci. USA99, 11399–11404 (2002).
21.
YuanF., ChenY., DellianM., SafabakhshN., FerraraN., JainR. K.Time-Dependent Vascular Regression and Permeability Changes in Established Human Tumor Xenografts Induced by an Anti-Vascular Endothelial Growth Factor/Vascular Permeability Factor Antibody. Proc. Natl. Acad. Sci. USA93, 14765–14770 (1996).
22.
WinklerF., KozinS. V., TongR. T., ChaeS. S., BoothM. F., GarkavtsevI., XuL., HicklinD. J., FukumuraD., di TomasoE., MunnL. L., JainR. K.Kinetics of Vascular Normalization by VEGFR2 Blockade Governs Brain Tumor Response to Radiation: Role of Oxygenation, Angiopoietin-1, and Matrix Metalloproteinases. Cancer Cell6, 553–563 (2004).
23.
TongR. T., BoucherY., KozinS. V., WinklerF., HicklinD. J., JainR. K.Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors. Cancer Research64, 3731–3736 (2004).
24.
NakamuraK., YamamotoA., KamishoharaM., TakahashiK., TaguchiE., MiuraT., KuboK., ShibuyaM., IsoeT.KRN633: A Selective Inhibitor of Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase That Suppresses Tumor Angiogenesis and Growth. Mol Cancer Ther3, 1639–1649 (2004).
25.
RosenL. S.Clinical Experience With Angiogenesis Signaling Inhibitors: Focus on Vascular Endothelial Growth Factor (VEGF) Blockers. Cancer Control9, 36–44 (2002).
26.
KabbinavarF., HurwitzH. I., FehrenbacherL., MeropolN. J., NovotnyW. F., LiebermanG., GriffingS., BergslandE.Phase II, Randomized Trial Comparing Bevacizumab Plus Fluorouracil (FU)/Leucovorin (LV) With FU/LV Alone in Patients With Metastatic Colorectal Cancer. Journal of Clinical Oncology21, 60–65 (2003).
27.
McCartyM. F., LiuW., FanF., ParikhA., ReimuthN., StoeltzingO., EllisL. M.Promises and Pitfalls of Anti-Angiogenic Therapy in Clinical Trials. Trends Mol. Med.9, 53–58 (2003).
DrixlerT. A., RinkesI. H., RitchieE. D., van VroonhovenT. J., GebbinkM. F., VoestE. E.Continuous Administration of Angiostatin Inhibits Accelerated Growth of Colorectal Liver Metastases After Partial Hepatectomy. Cancer Research60, 1761–1765 (2000).
30.
FeldmanA. L., LibuttiS. K.Progress in Antiangiogenic Gene Therapy of Cancer. Cancer89, 1181–1194 (2000).
31.
KongH. L., CrystalR. G.Gene Therapy Strategies for Tumor Antiangiogenesis. Journal of the National Cancer Institute90, 273–286 (1998).
32.
TandleA., BlazerD. G.III, LibuttiS. K.Antiangiogenic Gene Therapy of Cancer: Recent Developments. J. Transl. Med.2, 22-(2004).
33.
ZhangL., ChenQ. R., MixsonA. J.Antiangiogenic Gene Therapy in Cancer. Current Genomics1, 117–133 (2000).
AudouyS. A., de LeijL. F., HoekstraD., MolemaG.In Vivo Characteristics of Cationic Liposomes As Delivery Vectors for Gene Therapy. Pharmaceutical Research19, 1599–1605 (2002).
36.
XuM., KumarD., SrinivasS., DetollaL. J., YuS. F., StassS. A., MixsonA. J.Parenteral Gene Therapy With P53 Inhibits Human Breast Tumors In Vivo Through a Bystander Mechanism Without Evidence of Toxicity. Hum. Gene Ther8, 177–185 (1997).
37.
DingI., SunJ. Z., FentonB., LiuW. M., KimselyP., OkunieffP., MinW.Intratumoral Administration of Endostatin Plasmid Inhibits Vascular Growth and Perfusion in MCa-4 Murine Mammary Carcinomas. Cancer Research61, 526–531 (2001).
38.
OgaM., TakenagaK., SatoY., NakajimaH., KoshikawaN., OsatoK., SakiyamaS.Inhibition of Metastatic Brain Tumor Growth by Intramuscular Administration of the Endostatin Gene. International Journal of Oncology23, 73–79 (2003).
39.
GuZ. P., WangY. J., LiJ. G., ZhouY. A.VEGF165 Antisense RNA Suppresses Oncogenic Properties of Human Esophageal Squamous Cell Carcinoma. World J. Gastroenterol.8, 44–48 (2002).
40.
GuanH., ZhouZ., WangH., JiaS. F., LiuW., KleinermanE. S.A Small Interfering RNA Targeting Vascular Endothelial Growth Factor Inhibits Ewing's Sarcoma Growth in a Xenograft Mouse Model. Clinical Cancer Research11, 2662–2669 (2005).
41.
LiL., WartchowC. A., DanthiS. N., ShenZ., DecheneN., PeaseJ., ChoiH. S., DoedeT., ChuP., NingS., LeeD. Y., BednarskiM. D., KnoxS. J.A Novel Antiangiogenesis Therapy Using an Integrin Antagonist or Anti-Flk-1 Antibody Coated 90Y-Labeled Nanoparticles. International Journal of Radiation Oncology, Biology, Physics58, 1215–1227 (2004).
ThomasC. E., EhrhardtA., KayM. A.Progress and Problems With the Use of Viral Vectors for Gene Therapy. Nat. Rev. Genet.4, 346–358 (2003).
44.
44. Hacein-Bey-AbinaS., von KalleC., SchmidtM., McCormackM. P., WulffraatN., LeboulchP., LimA., OsborneC. S., PawliukR., MorillonE., SorensenR., ForsterA., FraserP., CohenJ. I., de SaintB. G., AlexanderI., WintergerstU., FrebourgT., AuriasA., Stoppa-LyonnetD., RomanaS., Radford-WeissI., GrossF., ValensiF., DelabesseE., MacintyreE., SigauxF., SoulierJ., LeivaL. E., WisslerM., PrinzC., RabbittsT. H., Le DeistF., FischerA., Cavazzana-CalvoM.LMO2-Associated Clonal T Cell Proliferation in Two Patients After Gene Therapy for SCID-X1. Science302, 415–419 (2003).
45.
KaplittM. G., LeoneP., SamulskiR. J., XiaoX., PfaffD. W., O'MalleyK. L., DuringM. J.Long-Term Gene Expression and Phenotypic Correction Using Adeno-Associated Virus Vectors in the Mammalian Brain. Nature Genetics8, 148–154 (1994).
46.
HerzogR. W., HagstromJ. N., KungS. H., TaiS. J., WilsonJ. M., FisherK. J., HighK. A.Stable Gene Transfer and Expression of Human Blood Coagulation Factor IX After Intramuscular Injection of Recombinant Adeno-Associated Virus. Proc. Natl. Acad. Sci. USA94, 5804–5809 (1997).
47.
KlauberN., RohanR. M., FlynnE., D'AmatoR. J.Critical Components of the Female Reproductive Pathway Are Suppressed by the Angiogenesis Inhibitor AGM-1470. Nat. Med.3, 443–446 (1997).
48.
KleinS. A., BondS. J., GuptaS. C., YacoubO. A., AndersonG. L.Angiogenesis Inhibitor TNP-470 Inhibits Murine Cutaneous Wound Healing. Journal of Surgical Research82, 268–274 (1999).
49.
ThorpeP. E.Vascular Targeting Agents As Cancer Therapeutics. Clinical Cancer Research10, 415–427 (2004).
50.
O'ReillyM. S., HolmgrenL., ShingY., ChenC., RosenthalR. A., CaoY., MosesM., LaneW. S., SageE. H., FolkmanJ.Angiostatin: A Circulating Endothelial Cell Inhibitor That Suppresses Angiogenesis and Tumor Growth. Cold Spring Harbor Symposia on Quantitative Biology59, 471–482 (1994).
51.
O'ReillyM. S., HolmgrenL., ShingY., ChenC., RosenthalR. A., MosesM., LaneW. S., CaoY., SageE. H., FolkmanJ.Angiostatin: A Novel Angiogenesis Inhibitor That Mediates the Suppression of Metastases by a Lewis Lung Carcinoma. Cell79, 315–328 (1994).
52.
CaoY., O'ReillyM. S., MarshallB., FlynnE., JiR. W., FolkmanJ.Expression of Angiostatin CDNA in a Murine Fibrosarcoma Suppresses Primary Tumor Growth and Produces Long-Term Dormancy of Metastases. J Clin. Invest101, 1055–1063 (1998).
53.
TanakaT., CaoY., FolkmanJ., FineH. A.Viral Vector-Targeted Antiangiogenic Gene Therapy Utilizing an Angiostatin Complementary DNA. Cancer Research58, 3362–3369 (1998).
54.
LalaniA. S., ChangB., LinJ., CaseS. S., LuanB., Wu-PriorW. W., VanRoeyM., JoossK.Anti-Tumor Efficacy of Human Angiostatin Using Liver-Mediated Adeno-Associated Virus Gene Therapy. Mol Ther9, 56–66 (2004).
55.
O'ReillyM. S., BoehmT., ShingY., FukaiN., VasiosG., LaneW. S., FlynnE., BirkheadJ. R., OlsenB. R., FolkmanJ.Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth. Cell88, 277–285 (1997).
56.
DutourA., MonteilJ., ParafF., CharissouxJ. L., KalettaC., SauerB., NaujoksK., RigaudM.Endostatin CDNA/Cationic Liposome Complexes as a Promising Therapy to Prevent Lung Metastases in Osteosarcoma: Study in a Human-Like Rat Orthotopic Tumor. Mol. Ther.11, 311–319 (2005).
57.
NoroT., MiyakeK., Suzuki-MiyakeN., IgarashiT., UchidaE., MisawaT., YamazakiY., ShimadaT.Adeno-Associated Viral Vector-Mediated Expression of Endostatin Inhibits Tumor Growth and Metastasis in an Orthotropic Pancreatic Cancer Model in Hamsters. Cancer Research64, 7486–7490 (2004).
58.
LawlerJ., DetmarM.Tumor Progression: The Effects of Thrombospondin-1 and-2. International Journal of Biochemistry and Cell Biology36, 1038–1045 (2004).
59.
JinR. J., KwakC., LeeS. G., LeeC. H., SooC. G., ParkM. S., LeeE., LeeS. E.The Application of an Anti-Angiogenic Gene (Thrombospondin-1) in the Treatment of Human Prostate Cancer Xenografts. Cancer Gene Therapy7, 1537–1542 (2000).
60.
HahnW., HoS. H., JeongJ. G., HahnE. Y., KimS., YuS. S., KimS., KimJ. M.Viral Vector-Mediated Transduction of a Modified Thrombospondin-2 CDNA Inhibits Tumor Growth and Angiogenesis. Gene Therapy11, 739–745 (2004).
61.
LiuP., WangY., LiY. H., YangC., ZhouY. L., LiB., LuS. H., YangR. C., CaiY. L., TobelemG., CaenJ., HanZ. C.Adenovirus-Mediated Gene Therapy With an Antiangiogenic Fragment of Thrombospondin-1 Inhibits Human Leukemia Xenograft Growth in Nude Mice. Leukemia Research27, 701–708 (2003).
62.
BrandK.Cancer Gene Therapy With Tissue Inhibitors of Metalloproteinases (TIMPs). Curr. Gene Ther.2, 255–271 (2002).
63.
JiangY., GoldbergI. D., ShiY. E.Complex Roles of Tissue Inhibitors of Metalloproteinases in Cancer. Oncogene21, 2245–2252 (2002).
64.
Anand-ApteB., PepperM. S., VoestE., MontesanoR., OlsenB., MurphyG., ApteS. S., ZetterB.Inhibition of Angiogenesis by Tissue Inhibitor of Metalloproteinase-3. Invest Ophthalmol. Vis. Sci.38, 817–823 (1997).
65.
SpurbeckW. W., NgC. Y., StromT. S., VaninE. F., DavidoffA. M.Enforced Expression of Tissue Inhibitor of Matrix Metalloproteinase-3 Affects Functional Capillary Morphogenesis and Inhibits Tumor Growth in a Murine Tumor Model. Blood100, 3361–3368 (2002).
66.
TranP. L., VigneronJ. P., PericatD., DuboisS., CazalsD., HervyM., DeClerckY. A., DegottC., AuclairC.Gene Therapy for Hepatocellular Carcinoma Using Non-Viral Vectors Composed of Bis Guanidinium-Tren-Cholesterol and Plasmids Encoding the Tissue Inhibitors of Metalloproteinases TIMP-2 and TIMP-3. Cancer Gene Ther10, 435–444 (2003).
67.
NorthS., MoennerM., BikfalviA.Recent Developments in the Regulation of the Angiogenic Switch by Cellular Stress Factors in Tumors. Cancer Letters218, 1–14 (2005).
68.
BouvetM., BoldR. J., LeeJ., EvansD. B., AbbruzzeseJ. L., ChiaoP. J., McConkeyD. J., ChandraJ., ChadaS., FangB., RothJ. A.Adenovirus-Mediated Wild-Type P53 Tumor Suppressor Gene Therapy Induces Apoptosis and Suppresses Growth of Human Pancreatic Cancer [Seecomments]. Annals of Surgical Oncology5, 681–688 (1998).
69.
NishizakiM., FujiwaraT., TanidaT., HizutaA., NishimoriH., TokinoT., NakamuraY., BouvetM., RothJ. A., TanakaN.Recombinant Adenovirus Expressing Wild-Type P53 Is Antiangiogenic: A Proposed Mechanism for Bystander Effect. Clinical Cancer Research5, 1015–1023 (1999).
70.
SalehM., DavisI. D., WilksA. F.The Paracrine Role of Tumour-Derived MIL-4 on Tumour-Associated Endothelium. International Journal of Cancer72, 664–672 (1997).
71.
SalehM., WiegmansA., MaloneQ., StylliS. S., KayeA. H.Effect of In Situ Retroviral Interleukin-4 Transfer on Established Intracranial Tumors. J Natl. Cancer Inst.91, 438–445 (1999).
72.
VoestE. E., KenyonB. M., O'ReillyM. S., TruittG., D'AmatoR. J., FolkmanJ.Inhibition of Angiogenesis In Vivo by Interleukin 12. J Natl. Cancer Inst.87, 581–586 (1995).
73.
PortieljeJ. E., KruitW. H., SchulerM., BeckJ., LamersC. H., StoterG., HuberC., Boer-DennertM., RakhitA., BolhuisR. L., AulitzkyW. E.Phase I Study of Subcutaneously Administered Recombinant Human Interleukin 12 in Patients With Advanced Renal Cell Cancer. Clinical Cancer Research5, 3983–3989 (1999).
74.
GollobJ. A., MierJ. W., VeenstraK., McDermottD. F., ClancyD., ClancyM., AtkinsM. B.Phase I Trial of Twice-Weekly Intravenous Interleukin 12 in Patients With Metastatic Renal Cell Cancer or Malignant Melanoma: Ability to Maintain IFN-Gamma Induction Is Associated With Clinical Response. Clinical Cancer Research6, 1678–1692 (2000).
75.
Asselin-PaturelC., LassauN., GuinebretiereJ. M., ZhangJ., GayF., BexF., HallezS., LeclereJ., PeronneauP., Mami-ChouaibF., ChouaibS.Transfer of the Murine Interleukin-12 Gene In Vivo by a Semliki Forest Virus Vector Induces B16 Tumor Regression Through Inhibition of Tumor Blood Vessel Formation Monitored by Doppler Ultrasonography. Gene Ther6, 606–615 (1999).
76.
WongR. J., ChanM. K., YuZ., GhosseinR. A., NgaiI., AdusumilliP. S., StilesB. M., ShahJ. P., SinghB., FongY.Angiogenesis Inhibition by an Oncolytic Herpes Virus Expressing Interleukin 12. Clinical Cancer Research10, 4509–4516 (2004).
77.
CaoR., FarneboJ., KurimotoM., CaoY.Interleukin-18 Acts As an Angiogenesis and Tumor Suppressor. FASEB Journal13, 2195–2202 (1999).
78.
NagaiH., HaraI., HorikawaT., OkaM., KamidonoS., IchihashiM.Gene Transfer of Secreted-Type Modified Interleukin-18 Gene to B16F10 Melanoma Cells Suppresses In Vivo Tumor Growth Through Inhibition of Tumor Vessel Formation. J. Invest Dermatol.119, 541–548 (2002).
79.
StreckC. J., ZhangY., MiyamotoR., ZhouJ., NgC. Y., NathwaniA. C., DavidoffA. M.Restriction of Neuroblastoma Angiogenesis and Growth by Interferon-Alpha/Beta. Surgery136, 183–189 (2004).
80.
DvorakH. F., GresserI.Microvascular Injury in Pathogenesis of Interferon-Induced Necrosis of Subcutaneous Tumors in Mice. Journal of the National Cancer Institute81, 497–502 (1989).
81.
SlatonJ. W., PerrotteP., InoueK., DinneyC. P., FidlerI. J.Interferon-Alpha-Mediated Down-Regulation of Angiogenesis-Related Genes and Therapy of Bladder Cancer Are Dependent on Optimization of Biological Dose and Schedule. Clinical Cancer Research5, 2726–2734 (1999).
82.
DinneyC. P., BielenbergD. R., PerrotteP., ReichR., EveB. Y., BucanaC. D., FidlerI. J.Inhibition of Basic Fibroblast Growth Factor Expression, Angiogenesis, and Growth of Human Bladder Carcinoma in Mice by Systemic Interferon-Alpha Administration. Cancer Research58, 808–814 (1998).
83.
IzawaJ. I., SweeneyP., PerrotteP., KedarD., DongZ., SlatonJ. W., KarashimaT., InoueK., BenedictW. F., DinneyC. P.Inhibition of Tumorigenicity and Metastasis of Human Bladder Cancer Growing in Athymic Mice by Interferon-Beta Gene Therapy Results Partially From Various Antiangiogenic Effects Including Endothelial Cell Apoptosis. Clin Cancer Res.8, 1258–1270 (2002).
84.
EinhornS., GranderD.Why Do So Many Cancer Patients Fail to Respond to Interferon Therapy?Journal of Interferon and Cytokine Research16, 275–281 (1996).
85.
StreckC. J., DicksonP. V., NgC. Y., ZhouJ., GrayJ. T., NathwaniA. C., DavidoffA. M.Adeno-Associated Virus Vector-Mediated Systemic Delivery of Interferon-â Combined With Low Dose Cyclophosphamide Effects Tumor Regression in Murine Neuroblastoma Models. Clinical Cancer Research (2005).
86.
StreckC. J., DicksonP. V., NgC. Y., ZhouJ., GrayJ. T., NathwaniA. C., DavidoffA. M.Anti-Tumor Efficacy of AAV-Mediated Systemic Delivery of Interferon-α. Cancer Gene Ther (2005).
87.
SalehM., JonasN. K., WiegmansA., StylliS. S.The Treatment of Established Intracranial Tumors by In Situ Retroviral IFN-Gamma Transfer. Gene Ther7, 1715–1724 (2000).
88.
MahasreshtiP. J., NavarroJ. G., KataramM., WangM. H., CareyD., SiegalG. P., BarnesM. N., NettelbeckD. M., AlvarezR. D., HemminkiA., CurielD. T.Adenovirus-Mediated Soluble FLT-1 Gene Therapy for Ovarian Carcinoma. Clinical Cancer Research7, 2057–2066 (2001).
89.
TakayamaK., UenoH., NakanishiY., SakamotoT., InoueK., ShimizuK., OohashiH., HaraN.Suppression of Tumor Angiogenesis and Growth by Gene Transfer of a Soluble Form of Vascular Endothelial Growth Factor Receptor into a Remote Organ. Cancer Research60, 2169–2177 (2000).
90.
DavidoffA. M., LearyM. A., NgC. Y., VaninE. F.Gene Therapy-Mediated Expression by Tumor Cells of the Angiogenesis Inhibitor Flk-1 Results in Inhibition of Neuroblastoma Growth In Vivo. J Pediatr Surg.36, 30–36 (2001).
91.
LydenD., HattoriK., DiasS., CostaC., BlaikieP., ButrosL., ChadburnA., HeissigB., MarksW., WitteL., WuY., HicklinD., ZhuZ., HackettN. R., CrystalR. G., MooreM. A., HajjarK. A., ManovaK., BenezraR., RafiiS.Impaired Recruitment of Bone-Marrow-Derived Endothelial and Hematopoietic Precursor Cells Blocks Tumor Angiogenesis and Growth. Nat. Med.7, 1194–1201 (2001).
92.
LiH., GeraldW. L., BenezraR.Utilization of Bone Marrow-Derived Endothelial Cell Precursors in Spontaneous Prostate Tumors Varies With Tumor Grade. Cancer Research64, 6137–6143 (2004).
93.
MurayamaT., TepperO. M., SilverM., MaH., LosordoD. W., IsnerJ. M., AsaharaT., KalkaC.Determination of Bone Marrow-Derived Endothelial Progenitor Cell Significance in Angiogenic Growth Factor-Induced Neovascularization In Vivo. Experimental Hematology30, 967–972 (2002).
94.
AnnabiB., NaudE., LeeY. T., EliopoulosN., GalipeauJ.Vascular Progenitors Derived From Murine Bone Marrow Stromal Cells Are Regulated by Fibroblast Growth Factor and Are Avidly Recruited by Vascularizing Tumors. J. Cell Biochem.91, 1146–1158 (2004).
95.
RajantieI., IlmonenM., AlminaiteA., OzerdemU., AlitaloK., SalvenP.Adult Bone Marrow-Derived Cells Recruited During Angiogenesis Comprise Precursors for Periendothelial Vascular Mural Cells. Blood104, 2084–2086 (2004).
96.
DavidoffA. M., NgC. Y., BrownP., LearyM. A., SpurbeckW. W., ZhouJ., HorwitzE., VaninE. F., NienhuisA. W.Bone Marrow-Derived Cells Contribute to Tumor Neovasculature and, When Modified to Express an Angiogenesis Inhibitor, Can Restrict Tumor Growth in Mice. Clinical Cancer Research7, 2870–2879 (2001).
97.
DavidoffA. M., NathwaniA. C., SpurbeckW. W., NgC. Y., ZhouJ., VaninE. F.RAAV-Mediated Long-Term Liver-Generated Expression of an Angiogenesis Inhibitor Can Restrict Renal Tumor Growth in Mice. Cancer Research62, 3077–3083 (2002).
98.
StreckC. J., ZhouJ., NgC. Y., ZhangY., NathwaniA. C., DavidoffA. M.Longterm Recombinant Adeno-Associated, Virus-Mediated, Liver-Generated Expression of an Angiogenesis Inhibitor Improves Survival in Mice With Disseminated Neuroblastoma. Journal of the American College of Surgeons199, 78–86 (2004).
99.
DavidoffA. M., NgC. Y., ZhangY., StreckC. J., MabryS. J., BartonS. H., BaudinoT., ZhouJ., KerbelR. S., VaninE. F., NathwaniA. C.Careful Decoy Receptor Titering Is Required to Inhibit Tumor Angiogenesis While Avoiding Adversely Altering VEGF Bioavailability. Mol Ther11, 300–310 (2005).
100.
AbdollahiA., LipsonK. E., SckellA., ZieherH., KlenkeF., PoerschkeD., RothA., HanX., KrixM., BischofM., HahnfeldtP., GroneH. J., DebusJ., HlatkyL., HuberP. E.Combined Therapy With Direct and Indirect Angiogenesis Inhibition Results in Enhanced Antiangiogenic and Antitumor Effects. Cancer Res63, 8890–8898 (2003).
101.
WildiersH., GuetensG., De BoeckG., VerbekenE., LanduytB., LanduytW., De BruijnE. A., Van OosteromA. T.Effect of Antivascular Endothelial Growth Factor Treatment on the Intratumoral Uptake of CPT-11. British Journal of Cancer88, 1979–1986 (2003).
102.
LuoX., AndresM. L., TimiryasovaT. M., FodorI., SlaterJ. M., GridleyD. S.Radiation-Enhanced Endostatin Gene Expression and Effects of Combination Treatment. Technol. Cancer Res. Treat.4, 193–202 (2005).
103.
HurwitzH., FehrenbacherL., NovotnyW., CartwrightT., HainsworthJ., HeimW., BerlinJ., BaronA., GriffingS., HolmgrenE., FerraraN., FyfeG., RogersB., RossR., KabbinavarF.Bevacizumab Plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. New England Journal of Medicine350, 2335–2342 (2004).
104.
WillettC. G., BoucherY., di TomasoE., DudaD. G., MunnL. L., TongR. T., ChungD. C., SahaniD. V., KalvaS. P., KozinS. V., MinoM., CohenK. S., ScaddenD. T., HartfordA. C., FischmanA. J., ClarkJ. W., RyanD. P., ZhuA. X., BlaszkowskyL. S., ChenH. X., ShellitoP. C., LauwersG. Y., JainR. K.Direct Evidence That the VEGF-Specific Antibody Bevacizumab Has Antivascular Effects in Human Rectal Cancer. Nat. Med.10, 145–147 (2004).
105.
JainR. K.Antiangiogenic Therapy for Cancer: Current and Emerging Concepts. Oncology (Huntingt)19, 7–16 (2005).
106.
YangA. D., BauerT. W., CampE. R., SomcioR., LiuW., FanF., EllisL. M.Improving Delivery of Antineoplastic Agents With Anti-Vascular Endothelial Growth Factor Therapy. Cancer103, 1561–1570 (2005).
