• 1
    Au JL, Jang SH, Zheng J, et al. Determinants of drug delivery and transport to solid tumors. J Control Release. 2001; 74(1–3): 3146.
  • 2
    Tannock IF, Lee CM, Tunggal JK, Cowan DS, Egorin MJ. Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy. Clin Cancer Res. 2002; 8: 878884.
  • 3
    Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer. 2004; 4: 806813.
  • 4
    Jain RK. Transport of molecules in the tumor interstitium: a review. Cancer Res. 1987; 47: 30393051.
  • 5
    Jain RK. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 1987; 6: 559593.
  • 6
    Boucher Y, Kirkwood JM, Opacic D, Desantis M, Jain RK. Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res. 1991; 51: 66916694.
  • 7
    Gutmann R, Leunig M, Feyh J, et al. Interstitial hypertension in head and neck tumors in patients: correlation with tumor size. Cancer Res. 1992; 52: 19931995.
  • 8
    Nathanson SD, Nelson L. Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma. Ann Surg Oncol. 1994; 1: 333338.
  • 9
    Boucher Y, Jain RK. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 1992; 52: 51105114.
  • 10
    Boucher Y, Leunig M, Jain RK. Tumor angiogenesis and interstitial hypertension. Cancer Res. 1996; 56: 42644246.
  • 11
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971; 285: 11821186.
  • 12
    Senger DR, Perruzzi CA, Feder J, Dvorak HF. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986; 46: 56295632.
  • 13
    Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002; 20: 43684380.
  • 14
    Ferrara N. VEGF: an update on biological and therapeutic aspects. Curr Opin Biotechnol. 2000; 11: 617624.
  • 15
    Stoeltzing O, Ellis LM. Regulators of vascular endothelial growth factor expression in cancer. Cancer Treat Res. 2004; 119: 3358.
  • 16
    Reinmuth N, Parikh AA, Ahmad SA, et al. Biology of angiogenesis in tumors of the gastrointestinal tract. Microsc Res Tech. 2003; 60: 199207.
  • 17
    Takeda A, Stoeltzing O, Ahmad SA, et al. Role of angiogenesis in the development and growth of liver metastasis. Ann Surg Oncol. 2002; 9: 610616.
  • 18
    Jain RK. Barriers to drug delivery in solid tumors. Sci Am. 1994; 271: 5865.
  • 19
    Baish JW, Jain RK. Fractals and cancer. Cancer Res. 2000; 60: 36833688.
  • 20
    Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2002; 160: 9851000.
  • 21
    Jain RK, Safabakhsh N, Sckell A, et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc Natl Acad Sci USA. 1998; 95: 1082010825.
  • 22
    Ashrafpour H, Huang N, Neligan PC, et al. Vasodilator effect and mechanism of action of vascular endothelial growth factor in skin vasculature. Am J Physiol Heart Circ Physiol. 2004; 286: H946H954.
  • 23
    Bates DO, Harper SJ. Regulation of vascular permeability by vascular endothelial growth factors. Vascul Pharmacol. 2002; 39(4–5): 225237.
  • 24
    Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004; 64: 37313736.
  • 25
    Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995; 146: 10291039.
  • 26
    Zhang H, Wu J, Meng L, Shou CC. Expression of vascular endothelial growth factor and its receptors KDR and Flt-1 in gastric cancer cells. World J Gastroenterol. 2002; 8: 994998.
  • 27
    Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med. 1999; 77: 527543.
  • 28
    Gerber HP, Hillan KJ, Ryan AM, et al. VEGF is required for growth and survival in neonatal mice. Development. 1999; 126: 11491159.
  • 29
    Zachary I. Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am J Physiol Cell Physiol. 2001; 280: C1375C1386.
  • 30
    Zachary I, Gliki G. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res. 2001; 49: 568581.
  • 31
    Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res. 2000; 60: 43244327.
  • 32
    Reis-Filho JS, Schmitt FC. Lymphangiogenesis in tumors: what do we know? Microsc Res Tech. 2003; 60: 171180.
  • 33
    Koura AN, Liu W, Kitadai Y, Singh RK, Radinsky R, Ellis LM. Regulation of vascular endothelial growth factor expression in human colon carcinoma cells by cell density. Cancer Res. 1996; 56: 38913894.
  • 34
    Pietras K, Sjéoblom T, Rubin K, Heldin CH, Ostman A. PDGF receptors as cancer drug targets. Cancer Cell. 2003; 3: 439443.
  • 35
    Pietras K. Increasing tumor uptake of anticancer drugs with imatinib. Semin Oncol. 2004; 31: 1823.
  • 36
    Gullberg D, Tingstréom A, Thuresson AC, et al. Beta 1 integrin-mediated collagen gel contraction is stimulated by PDGF. Exp Cell Res. 1990; 186: 264272.
  • 37
    Rodt SA, Ahlâen K, Berg A, Rubin K, Reed RK. A novel physiological function for platelet-derived growth factor-BB in rat dermis. J Physiol. 1996; 495: 193200.
  • 38
    Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999; 79: 12831316.
  • 39
    Heuchel R, Berg A, Tallquist M, et al. Platelet-derived growth factor beta receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3′ kinase signaling. Proc Natl Acad Sci USA. 1999; 96: 1141011415.
  • 40
    Ellis LM, Liu W, Wilson M. Down-regulation of vascular endothelial growth factor in human colon carcinoma cell lines by antisense transfection decreases endothelial cell proliferation. Surgery. 1996; 120: 871878.
  • 41
    Ellis LM, Liu W, Fan F, et al. Role of angiogenesis inhibitors in cancer treatment. Oncology (Huntingt). 2001; 15: 3946.
  • 42
    Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 2000; 60: 62536258.
  • 43
    Klohs WD, Hamby JM. Antiangiogenic agents. Curr Opin Biotechnol. 1999; 10: 544549.
  • 44
    Dias S, Hattori K, Heissig B, et al. Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA. 2001; 98: 1085710862.
  • 45
    Ebos JM, Tran J, Master Z, et al. Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia. Mol Cancer Res. 2002; 1: 8995.
  • 46
    Bruns CJ, Shrader M, Harbison MT, et al. Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice. Int J Cancer. 2002; 102: 101108.
  • 47
    Zhu Z, Lu D, Kotanides H, et al. Inhibition of vascular endothelial growth factor induced mitogenesis of human endothelial cells by a chimeric anti-kinase insert domain-containing receptor antibody. Cancer Lett. 1999; 136: 203213.
  • 48
    Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer. 2001; 85: 584589.
  • 49
    Shaheen RM, Tseng WW, Vellagas R, et al. Effects of an antibody to vascular endothelial growth factor receptor-2 on survival, tumor vascularity, and apoptosis in a murine model of colon carcinomatosis. Int J Oncol. 2001; 18: 221226.
  • 50
    Teicher BA, Holden SA, Ara G, et al. Influence of an anti-angiogenic treatment on 9L gliosarcoma: oxygenation and response to cytotoxic therapy. Int J Cancer. 1995; 61: 732737.
  • 51
    Shishido T, Yasoshima T, Denno R, Mukaiya M, Sato N, Hirata K. Inhibition of liver metastasis of human pancreatic carcinoma by angiogenesis inhibitor TNP-470 in combination with cisplatin. Jpn J Cancer Res. 1998; 89: 963969.
  • 52
    Satoh H, Ishikawa H, Fujimoto M, et al. Combined effects of TNP-470 and taxol in human non-small cell lung cancer cell lines. Anticancer Res. 1998; 18(2A): 10271030.
  • 53
    Hu L, Hofmann J, Zaloudek C, Ferrara N, Hamilton T, Jaffe RB. Vascular endothelial growth factor immunoneutralization plus paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol. 2002; 161: 19171924.
  • 54
    Wild R, Dings RP, Subramanian I, Ramakrishnan S. Carboplatin selectively induces the VEGF stress response in endothelial cells: potentiation of antitumor activity by combination treatment with antibody to VEGF. Int J Cancer. 2004; 110: 343351.
  • 55
    Sweeney CJ, Miller KD, Sissons SE, et al. The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res. 2001; 61: 33693372.
  • 56
    Kerbel RS, Klement G, Pritchard KI, Kamen B. Continuous low-dose anti-angiogenic/metronomic chemotherapy: from the research laboratory into the oncology clinic. Ann Oncol. 2002; 13: 1215.
  • 57
    Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004; 4: 423436.
  • 58
    Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy [see comment]. Nat Med. 2001; 7: 987989.
  • 59
    Hansen-Algenstaedt N, Stoll BR, Padera TP, et al. Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy. Cancer Res. 2000; 60: 45564560.
  • 60
    Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004; 10: 145147.
  • 61
    Huang J, Frischer JS, Serur A, et al. Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc Natl Acad Sci USA. 2003; 100: 77857790.
  • 62
    Vajkoczy P, Menger MD, Vollmar B, et al. Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy. Neoplasia. 1999; 1: 3141.
  • 63
    Kan Z, Phongkitkarun S, Kobayashi S, et al. Value of functional CT for quantifying tumor perfusion in antiangiogenic therapy in a rat model. The Radiological Society of North America 89th Scientific Assembly and Annual Meeting, 2003.
  • 64
    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: 159165.
  • 65
    Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001; 19: 843850.
  • 66
    Kerbel RS, Viloria-Petit A, Klement G, Rak J. ‘Accidental’ anti-angiogenic drugs. anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. Eur J Cancer. 2000; 36: 12481257.
  • 67
    Solorzano CC, Baker CH, Bruns CJ, et al. Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Cancer Biother Radiopharm. 2001; 16: 359370.
  • 68
    Sweeney P, Karashima T, Kim SJ, et al. Anti-vascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production. Clin Cancer Res. 2002; 8: 27142724.
  • 69
    Inoue K, Slaton JW, Davis DW, et al. Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel. Clin Cancer Res. 2000; 6: 26352643.
  • 70
    Ma J, Li S, Reed K, Guo P, Gallo JM. Pharmacodynamic-mediated effects of the angiogenesis inhibitor SU5416 on the tumor disposition of temozolomide in subcutaneous and intracerebral glioma xenograft models. J Pharmacol Exp Ther 2003; 305: 833839.
  • 71
    Wildiers H, Guetens G, De Boeck G, et al. Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer. 2003; 88: 19791986.
  • 72
    Lee CG, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 2000; 60: 55655570.
  • 73
    Gorski DH, Mauceri HJ, Salloum RM, et al. Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res. 1998; 58: 56865689.
  • 74
    Mauceri HJ, Hanna NN, Beckett MA, et al. Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature. 1998; 394: 287291.
  • 75
    Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res. 1999; 59: 33743378.
  • 76
    Gorski DH, Mauceri HJ, Salloum RM, Halpern A, Seetharam S, Weichselbaum RR. Prolonged treatment with angiostatin reduces metastatic burden during radiation therapy. Cancer Res. 2003; 63: 308311.
  • 77
    Kozin SV, Boucher Y, Hicklin DJ, Bohlen P, Jain RK, Suit HD. Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res. 2001; 61: 3944.
  • 78
    Hess C, Vuong V, Hegyi I, et al. Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth. Br J Cancer. 2001; 85: 20102016.
  • 79
    Geng L, Donnelly E, McMahon G, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res. 2001; 61: 24132419.
  • 80
    Zhu AX, Willett CG. Chemotherapeutic and biologic agents as radiosensitizers in rectal cancer. Semin Radiat Oncol. 2003; 13: 454468.
  • 81
    Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996; 56: 100104.
  • 82
    Buchdunger E, O'Reilly T, Wood J. Pharmacology of imatinib (STI571). Eur J Cancer. 2002; 38: S28S36.
  • 83
    Savage DG, Antman KH. Imatinib mesylate—a new oral targeted therapy. N Engl J Med. 2002; 346: 683693.
  • 84
    Pietras K, Stumm M, Hubert M, et al. STI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake. Clin Cancer Res. 2003; 9: 37793787.
  • 85
    Pietras K, Ostman A, Sjéoquist M, et al. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 2001; 61: 29292934.
  • 86
    Pietras K, Rubin K, Sjéoblom T, et al. Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res. 2002; 62: 54765484.
  • 87
    Griffon-Etienne G, Boucher Y, Brekken C, Suit HD, Jain RK. Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. Cancer Res. 1999; 59: 37763782.
  • 88
    Boucher Y, Salehi H, Witwer B, Harsh GR, Jain RK. Interstitial fluid pressure in intracranial tumours in patients and in rodents. Br J Cancer. 1997; 75: 829836.
  • 89
    Kristjansen PE, Boucher Y, Jain RK. Dexamethasone reduces the interstitial fluid pressure in a human colon adenocarcinoma xenograft. Cancer Res. 1993; 53: 47644766.
  • 90
    Rubin K, Sjoquist M, Gustafsson AM, Isaksson B, Salvessen G, Reed RK. Lowering of tumoral interstitial fluid pressure by prostaglandin E(1) is paralleled by an increased uptake of (51)Cr-EDTA. Int J Cancer. 2000; 86: 636643.
  • 91
    Salnikov AV, Iversen VV, Koisti M, et al. Lowering of tumor interstitial fluid pressure specifically augments efficacy of chemotherapy. FASEB J. 2003; 17: 17561758.
  • 92
    Lammerts E, Roswall P, Sundberg C, et al. Interference with TGF-beta1 and -beta3 in tumor stroma lowers tumor interstitial fluid pressure independently of growth in experimental carcinoma. Int J Cancer. 2002; 102: 453462.
  • 93
    Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004; 6: 553563.