Abstract
The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 × 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 × 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-disfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative antitumoural effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Asano M, Yukita A, Matsumoto T, Kondo S and Suzuki H (1995) Inhibition of tumour growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor-121. Cancer Res 55: 5296–5301
Borgestrom P, Hillan KJ, Sriramarao P and Ferrara N (1996) Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody; novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res 56: 4032–4039
Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Senger DR and Dvorak HF (1993a) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 53: 4727–4735
Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF and Senger DR (1993b) Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 143: 1255–1262
Clauss M, Weich H, Breier G, Knies U, Rockl W, Waltenberger J and Risau W (1996) The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 271: 17629–17634
Drevs J, Hofmann I, Hugenschmidt H, Wittig C, Madjar H, Muller M, Wood J, Martiny-Baron G, Unger C and Marme D (2000) Effects of PTK787/ZK222584/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumour, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res 60: 4819–4824
Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27–31
Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth KP and McMahon G (1999) SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumour vascularization, and growth of multiple tumour types. Cancer Res 59: 99–106
Geng L, Donnely E, McMahon G, Lin PC, Sierra-Rivera E, Oshinka H and Hallahan DE (2001) Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumour resistance to radiotherapy. Cancer Res 61: 2413–2419
Goldman CK, Kendall RL, Cabrera G, Soroceanu L, Heike Y, Gillesie GY, Siegal GP, Mao X, Bett AJ, Huckle WR, Thomas KA and Curiel DT (1998) Paracrine expression of an native soluble vascular endothelial growth factor receptor inhibits tumour growth, metastasis, and mortality rate. Proc Natl Acad Sci USA 95: 8795–8800
Gorski DH, Mauceri HJ, Salloum RM, Gately S, Hellman S, Beckett MA, Sukhatme VP, Soff GA, Kufe DW and Weichselbaum RR (1998) Potentiation of the antitumor effect of ionising radiation by brief concomitant exposures to angiostatin. Cancer Res 58: 5686–5689
Gorski DH, Beckett MA, Jaskowiak NT, Calvin DP, Mauceri HJ, Salloum RM, Seetharam S, Koons A, Hari DM, Kufe DW and Weichselbaum RR (1999) Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionising radiation. Cancer Res 59: 3374–3378
Hanahan D and Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364
Joukov V, Kaipainen A, Jeltsch M, Pajusola K, Olofsson B, Kumar V, Eriksson U and Alitalo K (1997) Vascular endothelial growth factors VEGF-B and VEGF-C. J Cell Physiol 173: 211–215
Kanai T, Konno H, Tanaka T, Baba M, Matsumoto K, Nakamura S, Yukita A, Asano M, Suzuki H and Baba S (1998) Anti-tumour and anti-metastatic effect of human-vascular-endothelial-growth-factor-neutralizing antibody on human colon and gastric carcinoma xenotransplantation orthotopically into nude mice. Int J Cancer 77: 933–936
Kim KJ, Li BB, Winer J, Armanini M, Gillett N, Phillips HS and Ferrara N (1993) Inhibition of vascular endothelial growth-factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362: 841–844
Kozin SV, Boucher Y, Hicklin DJ, Bohlen P, Jain RK and Suit HD (2001) Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumour xenografts. Cancer Res 61: 39–44
Kroll J and Waltenberger J (1997) The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem 272: 32521–32527
Lund EL, Bastholm L and Kristjansen PEG (2000) Therapeutic synergy of TNP-40 and ionising radiation: effects on tumour growth, vessel morphology and angiogenesis in human glioblastoma multiforme xenografts. Clin Cancer Res 6: 971–978
Mauceri HJ, Hanna NN, Beckett MA, Gorski DH, Staba MJ, Stellato KA, Bigelow K, Heimann R, Gately S, Dhanabal M, Soff GA, Sukhatme VP, Kufe DW and Weichselbaum RR (1998) Combined effects of angiostatin and ionising radiation in antitumour therapy. Nature 394: 287–291
Olofsson B, Pajusola K, Kaipainen A, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K and Eriksson U (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93: 2576–2581
Olofsson B, Korpelainen E, Pepper MS, Mandriota SJ, Aase K, Kumar V, Gunji Y, Jeltsch MM, Shibuya M, Alitalo K and Eriksson U (1998) Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Sci USA 95: 11709–11714
Park JE, Chen HH, Winer J, Houck KA and Ferrara N (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269: 25646–25654
Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H and Sato M (1990) Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 5: 519–524
Shibuya M (1995) Role of VEGF-flt receptor system in normal and tumour angiogenesis. Adv Cancer Res 67: 281–316
Sun L-Q, Li Y-X, Guillou L and Coucke PA (1998) (E)-2'-Deoxy-2'-(fluoromethylene) Cytidine potentiates radioresponse of two human solid tumour xenografts. Cancer Res 58: 5411–5417
Takahashi T and Shibuya M (1997) The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene 14: 2079–2089
Teicher BA, Holden SA, Ara G, Korbut T and Menon K (1996) Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma. Cancer Chemother Pharmacol 38: 169–177
Terman BI, Dougher VM, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D and Bohlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187: 1579–1586
UKCCR (1998) United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) Guidelines for the Welfare of Animals in Experimental Neoplasia 2nd edn. Bri J Cancer 77: 1–10
Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, Hofmann F, Mestan J, Mett H, O’Reilly T, Persohn E, Rosel J, Schnell C, Stover D, Theuer A, Towbin H, Wenger F, Woods-Cook K, Menrad A, Siemeister G, Schirner M, Thierauch KH, Schneider MR, Drevs J, Martiny-Baron G and Totzke F (2000) PTK787/ZK222584/ZK 222584 a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumour growth after oral administration. Cancer Res 60: 2178–2189
Yamada Y, Nezu J, Shimane M and Hirata Y (1997) Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. Genomics 42: 483–488
Zaugg K, Rocha S, Resch H, Hegyi I, Oehler C, Glanzmann C, Fabbro D, Bodis S and Pruschy M (2001) Differential, p53-dependent mechanism of radiosensitization in vitro and in vivo by the protein kinase C-specific inhibitor PKC412. Cancer Res 61: 732–738
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Hess, C., Vuong, V., Hegyi, I. et al. Effect of VEGF receptor inhibitor PTK787/ZK222548 combined with ionizing radiation on endothelial cells and tumour growth. Br J Cancer 85, 2010–2016 (2001). https://doi.org/10.1054/bjoc.2001.2166
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.2166
Keywords
This article is cited by
-
Interfering with Tumor Hypoxia for Radiotherapy Optimization
Journal of Experimental & Clinical Cancer Research (2021)
-
Angiogenic regeneration defines loco-regional recurrence following pre-operative radio-chemotherapy for rectal cancer: a pilot study
Molecular Biology Reports (2019)
-
Unexpected late radiation neurotoxicity following bevacizumab use: a case series
Journal of Neuro-Oncology (2011)
-
BMS-690514, a VEGFR and EGFR tyrosine kinase inhibitor, shows anti-tumoural activity on non-small-cell lung cancer xenografts and induces sequence-dependent synergistic effect with radiation
British Journal of Cancer (2010)
-
Vascular endothelial growth factor inhibitors in malignant gliomas
Targeted Oncology (2010)