Skip to main content

Advertisement

Springer Nature Link
Log in

Enhancing the therapeutic responsiveness of photodynamic therapy with the antiangiogenic agents SU5416 and SU6668 in murine nasopharyngeal carcinoma models

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Background: Photodynamic therapy (PDT) is a promising therapeutic modality using a tumor localizing photosensitizer and light to destroy tumor cells. A major limitation of PDT is tumor recurrence, which is partly due to neovascularization. Purpose: The objective of the present study was to determine whether combination therapy with PDT and antiangiogenic agents (i.e. SU5416 and SU6668) would be more effective in controlling tumor recurrence in a mouse model of human CNE2 poorly differentiated nasopharyngeal carcinoma compared with PDT or antiangiogenic agents administered alone. Methods: Athymic mice bearing CNE2 tumor xenografts received daily i.p. injections of 20 mg/kg SU5416 or 100 mg/kg SU6668 for 28 consecutive days either alone or following a single hypericin-PDT treatment. Results: Significant inhibition of CNE2 tumor growth was observed in all treatment groups. Differences in 4× tumor growth time, the number of mice with 4× tumor growth, tumor growth inhibition as well as the percent of mice surviving were not statistically significant among individual treatment groups. However, the number of mice with 4× tumor growth observed in SU6668 monotherapy and combined PDT and SU6668 treatment groups was significantly less than that in the control group (P<0.05 and 0.01, respectively). Moreover, compared with the control group, only the combined PDT and SU6668 treatment significantly extended survival of tumor-bearing host mice (P<0.05). The semiquantitative RT-PCR results showed that the expression of HIF-1α, VEGF, COX-2 and bFGF were increased in PDT-treated tumor samples collected 24 h post-PDT, suggesting that PDT-induced damage to tumor microvasculature and the resultant hypoxia upregulate the expression of certain proangiogenic factors. Conclusions: The effectiveness of PDT can be enhanced by antiangiogenic treatment with the synthetic RTK inhibitors. Of the two synthetic RTK inhibitors tested, SU6668 was more effective than SU5416 in enhancing tumor responsiveness to PDT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

bFGF:

Basic fibroblast growth factor

CCE:

Choriocapillaris endothelial

COX-2:

Cyclooxygenase-2

FGFR1:

Basic fibroblast growth factor receptor-1

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HIF-1:

Hypoxia-inducible factor 1

i.p.:

Intraperitoneal

NPC:

Nasopharyngeal carcinoma

PDGF:

Platelet derived growth factor

PDGFR :

Platelet derived growth factor receptor

PDT:

Photodynamic therapy

RTK:

Receptor-associated tyrosine kinase

TK:

Tyrosine kinase

VEGF:

Vascular endothelial growth factor

VEGFR-2:

Vascular endothelial growth factor receptor 2

References

  1. Ausprunk DH, Folkman J (1997) Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc Res 14:53–65

    Google Scholar 

  2. Chan WS, Brasseur N, La Madeleine C, van Lier JE (1996) Evidence for different mechanisms of EMT-6 tumor necrosis by photodynamic therapy with disulfonated aluminum phthalocyanine or photofrin: tumor cell survival and blood flow. Anticancer Res 16:1887–1892

    CAS  PubMed  Google Scholar 

  3. Chen B, Zupko I, de Witte PA (2001) Photodynamic therapy with hypericin in a mouse P388 tumor model: vascular effects determine the efficacy. Int J Oncol 18:737–742

    CAS  PubMed  Google Scholar 

  4. Chen Q, Huang Z, Chen H, Shapiro H, Beckers J, Hetzel FW (2002) Improvement of tumor response by manipulation of tumor oxygenation during photodynamic therapy. Photochem Photobiol 76:197–203

    CAS  PubMed  Google Scholar 

  5. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L (2003) VEGF-receptor signal transduction. Trends Biochem Sci 28:488–494

    CAS  PubMed  Google Scholar 

  6. Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S, Altman R and Giaccia AJ (2003) Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 22:5907–5914

    CAS  PubMed  Google Scholar 

  7. Dimitroff CJ, Klohs W, Sharma A, Pera P, Driscoll D, Veith J, Steinkampf R, Schroeder M, Klutchko S, Sumlin A, Henderson B, Dougherty TJ, Bernacki RJ (1999) Anti-angiogenic activity of selected receptor tyrosine kinase inhibitors, PD166285 and PD173074: implications for combination treatment with photodynamic therapy. Invest New Drugs 17: 121–135

    CAS  PubMed  Google Scholar 

  8. Dougherty TJ (1996) A brief history of clinical photodynamic therapy development at Roswell Park Cancer Institute. J Clin Laser Med 14:219–221

    CAS  Google Scholar 

  9. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q (1998) Photodynamic therapy. Natl Cancer Inst 90:889–905

    CAS  Google Scholar 

  10. Du HY, Bay BH, Olivo M (2003) Biodistribution and photodynamic therapy with hypericin in a human NPC murine tumor model. Int J Oncol 22:1019–1024

    CAS  PubMed  Google Scholar 

  11. Ferrario A, von Tiehl KF, Rucker N, Schwarz MA, Gill PS, Gomer CJ (2000) Antiangiogenic treatment enhances photodynamic therapy responsiveness in a mouse mammary carcinoma. Cancer Res 60:4066–4069

    CAS  PubMed  Google Scholar 

  12. Folkman J (1995) Tumour angiogensis. In: Mendelsohn J, Howley PM, Liotta MA (eds) Themolecular basis of cancer. WB Sanders, Philadelphia, pp 206–232

    Google Scholar 

  13. Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth KP, 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, tumor vascularization, and growth of multiple tumor types. Cancer Res 59:99–106

    CAS  PubMed  Google Scholar 

  14. Henderson BW, Dougherty TJ (1992) How does photodynamic therapy work?. Photochem Photobiol 55:145–157

    CAS  PubMed  Google Scholar 

  15. Henderson BW, Vaughan L, Bellnier DA, van Leengoed H, Johnson PG, Oseroff AR (1995) Photosensitization of murine tumor, vasculature and skin by 5-aminolevulinic acid-induced porphyrin. Photochem Photobiol 62: 780–789

    CAS  PubMed  Google Scholar 

  16. Itokawa T, Nokihara H, Nishioka Y, Sone S, Iwamoto Y, Yamada Y, Cherrington J, McMahon G, Shibuya M, Kuwano M, Ono M (2002) Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling. Mol Cancer Ther 1:295–302

    CAS  PubMed  Google Scholar 

  17. Kessel D (1990) HPD structure and determinants of localization. In: Kessel D (ed) Photodynamic therapy of neoplastic diseases. CRC, Boca Raton, pp 1–14

    Google Scholar 

  18. Laird AD, Vajkoczy P, Shawver LK, Thurnher A, Liang C, Mohammadi M, Schlessinger J, Ullrich A, Hubbard SR, Blake RA, Fong TA, Strawn LM, Sun L, Tang C, Hawtin R, Tang F, Shenoy N, Hirth KP, McMahon G, Cherrington JM (2000) SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 60:4152–4160

    CAS  PubMed  Google Scholar 

  19. Laird AD, Christensen JG, Li G, Carver J, Smith K, Xin X, Moss KG, Louie SG, Mendel DB, Cherrington JM (2002) SU6668 inhibits Flk-1/KDR and PDGFRß in vivo, resulting in rapid apoptosis of tumor vasculature and tumor regression in mice. FASEB J 16:681–690

    CAS  PubMed  Google Scholar 

  20. Lofgren LA, Hallgren S, Nilsson E, Westerborn A, Nilsson C, Reizenstein J (1995) Photodynamic therapy for recurrent nasopharyngeal cancer. Arch Otolaryngol Head Neck Surg 121:997–1002

    CAS  PubMed  Google Scholar 

  21. Lukiw WJ, Ottlecz A, Lambrou G, Grueninger M, Finley J, Thompson HW and Bazan NG (2003) Coordinate activation of HIF-1 and NF-kappaB DNA binding and COX-2 and VEGF expression in retinal cells by hypoxia. Invest Ophthalmol Vis Sci 44:4163–4170

    PubMed  Google Scholar 

  22. Lund EL, Bastholm L, Kristjansen PE (2000) Therapeutic synergy of TNP-470 and ionizing radiation: effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multiforme xenografts. Clin Cancer Res 6:971–978

    CAS  PubMed  Google Scholar 

  23. Mendel DB, Laird AD, Smolich BD, Blake RA, Liang C, Hannah AL,Shaheen RM, Ellis LM, Weitman S, Shawver LK, Cherrington JM (2000) Development of SU5416, a selective small molecule inhibitor of VEGFreceptor tyrosine kinase activity, as an anti-angiogenesis agent. Anticancer Drugs 15:29–41

    CAS  Google Scholar 

  24. Mendel DB, Schreck RE, West DC, Li G, Strawn LM, Tanciongco SS, Vasile S, Shawver LK, Cherrington JM (2000) The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function. Clin Cancer Res 6:4848–4858

    CAS  PubMed  Google Scholar 

  25. Nelson JS, Liaw LH, Orenstein A, Roberts WG, Berns MW (1988) Mechanism of tumor destruction following photodynamic therapy with hematoporphyrin derivative, chlorin, and phthalocyanine. J Natl Cancer Inst 80:1599–1605

    CAS  PubMed  Google Scholar 

  26. Ning S, Laird D, Cherrington JM, Knox SJ (2002) The antiangiogenic agents SU5416 and SU6668 increase the antitumor effects of fractionated irradiation. Radiat Res 157:45–51

    CAS  PubMed  Google Scholar 

  27. Peterson AC, Swiger S, Stadler WM, Medved M, Karczmar G, Gajewski TF (2004) Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma. Clin Cancer Res 10:4048–4054

    CAS  PubMed  Google Scholar 

  28. Schouwink H, Oppelaar H, Ruevekamp M, van der Valk M, Hart G, Rijken P, Baas P, Stewart FA (2003) Oxygen depletion during and after mTHPC-mediated photodynamic therapy in RIF1 and H-MESO1 tumors. Radiat Res 159:190–198

    CAS  PubMed  Google Scholar 

  29. Semenza GL (2000) Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 35:71–103

    CAS  PubMed  Google Scholar 

  30. Shaheen RM, Davis DW, Liu W, Zebrowski BK, Wilson MR, Bucana CD, McConkey DJ, McMahon G, Ellis LM (1999) Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer Res 59:5412–5416

    CAS  PubMed  Google Scholar 

  31. Sibata CH, Colussi VC, Oleinick NL, Kinsella TJ (2001) Photodynamic therapy in oncology. Expert Opin Pharmacother 2:917–927

    CAS  PubMed  Google Scholar 

  32. Stadler WM, Cao D, Vogelzang NJ, Ryan CW, Hoving K, Wright R, Karrison T, Vokes EE (2004) A randomized Phase II trial of the antiangiogenic agent SU5416 in hormone-refractory prostate cancer. Clin Cancer Res 10:3365–3370

    CAS  PubMed  Google Scholar 

  33. Star WM, Marijnissen HP, van den Berg-Blok AE, Versteeg JA, Franken KA, Reinhold HS (1986) Destruction of rat mammary tumor and normal tissue microcirculation by hematoporphyrin derivative photoradiation observed in vivo in sandwich observation chambers. Cancer Res 46:2532–2540

    CAS  PubMed  Google Scholar 

  34. Stanbridge EJ, Nowell PC (1990) Origins of human cancer revisited. Cell 63:867–874

    CAS  PubMed  Google Scholar 

  35. Tong MC, van Hasselt CA, Woo JK (1996) Preliminary results of photodynamic therapy for recurrent nasopharyngeal carcinoma. Eur Arch Otorhinolaryngol 253:189–192

    CAS  PubMed  Google Scholar 

  36. Vajkoczy P, Menger MD, Vollmar B, Schilling L, Schmiedek P, Hirth KP, Ullrich A, Fong TA (1999) Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy. Neoplasia 1:31–41

    CAS  PubMed  Google Scholar 

  37. Weinberg RA (1989) Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res 49:3713–3721

    CAS  PubMed  Google Scholar 

  38. Wenger RH, Gassmann M (1997) Oxygenes and the hypoxia-inducible factor-1. Biol Chem 378:609–616

    CAS  PubMed  Google Scholar 

  39. Yu MC, Yuan JM (2002) Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol 12:421–429

    PubMed  Google Scholar 

  40. Zangari M, Anaissie E, Stopeck A, Morimoto A, Tan N, Lancet J, Cooper M, Hannah A, Garcia-Manero G, Faderl S, Kantarjian H, Cherrington J, Albitar M, Giles FJ (2004) Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma. Clin Cancer Res 10:88–95

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Clinical Pharmacology Division of Clinical Trials & Epidemiological Sciences, National Cancer Centre, 11, Hospital Drive, 169610, Singapore

    Qingyu Zhou & Balram Chowbay

  2. Laboratory of Photodynamic Diagnosis and Treatment, Division of Medical Sciences, National Cancer Centre, Singapore

    Malini Olivo & Karen Yee Kar Lye

  3. Laboratory of Brain Tumour Research, Division of Medical Sciences, National Cancer Centre, Singapore

    Shirley Moore

  4. Department of Clinical PK/PD, Pfizer Inc, Groton, CT, 06385, USA

    Amarnath Sharma

Authors
  1. Qingyu Zhou
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Malini Olivo
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Karen Yee Kar Lye
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Shirley Moore
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Amarnath Sharma
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Balram Chowbay
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Balram Chowbay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, Q., Olivo, M., Lye, K.Y.K. et al. Enhancing the therapeutic responsiveness of photodynamic therapy with the antiangiogenic agents SU5416 and SU6668 in murine nasopharyngeal carcinoma models. Cancer Chemother Pharmacol 56, 569–577 (2005). https://doi.org/10.1007/s00280-005-1017-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-005-1017-0

Keywords