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Quantitative comparison of the inhibitory effects of GW5638 and tamoxifen on angiogenesis in the cornea pocket assay

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Abstract

GW5638 is a novel tissue-selective estrogen receptor (ER) modulator. Structurally, it is a derivative of tamoxifen that is known for its inhibitory effects on angiogenesis in an ER-independent manner. Therefore, it is possible that GW5638 has the same effects as tamoxifen on angiogenesis. To test this hypothesis, we used the rat cornea pocket assay and developed a new method that could precisely determine the total projected area of microvessels induced by basic fibroblast growth factor (bFGF) in the cornea. Animals in the study were treated with corn oil (control group), tamoxifen, or GW5638. After treatment, we observed that both GW5638 and tamoxifen could inhibit angiogenesis in the cornea (P<0.05) and that the inhibitory effects were not mediated by blocking functions of estrogen. Meanwhile, GW5638 had minimal effects on the body weight of animals whereas tamoxifen significantly reduced the body weight. Based on these observations, we concluded that GW5638 was as effective as tamoxifen in antiangiogenic treatment but less toxic than tamoxifen.

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Abbreviations

ER:

estrogen receptor

bFGF:

basic fibroblast growth factor

PBS:

phosphate buffered saline

References

  1. Willson TM, Norris JD et al. (1997) Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone. Endocrinology 138:3901–11

    Article  PubMed  CAS  Google Scholar 

  2. Howell A (2001) Future use of selective estrogen receptor modulators and aromatase inhibitors. Clin Cancer Res 7:4402s–10s

    PubMed  CAS  Google Scholar 

  3. Bentrem D, Dardes R, Liu H et al. (2001) Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen. Endocrinol 142:838–46

    Article  CAS  Google Scholar 

  4. Connor CE, Norris JD, Broadwater G et al. (2001) Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor. Cancer Res 61:2917–22

    PubMed  CAS  Google Scholar 

  5. Gagliardi AR, Hennig B, Collins DC (1996) Antiestrogens inhibit endothelial cell growth stimulated by angiogenic growth factors. Anticancer Res 16:1101–6

    PubMed  CAS  Google Scholar 

  6. Manolopoulos VG, Liekens S, Koolwijk P et al. Inhibition of angiogenesis by blockers of volume-regulated anion channels. Gen Pharmacol 2000; 34: 107–16

    Google Scholar 

  7. Kayyali R, Marriott C, Wiseman H (1994) Tamoxifen decreases drug efflux from liposomes: Relevance to its ability to reverse multidrug resistance in cancer cells? FEBS Lett 344:221–4

    Article  PubMed  CAS  Google Scholar 

  8. Custodio JB, Dinis TC, Almeida LM, Madeira VM (1994) Tamoxifen and hydroxytamoxifen as intramembraneous inhibitors of lipid peroxidation: Evidence for peroxyl radical scavenging activity. Biochem Pharmacol 47:1989–98

    Article  PubMed  CAS  Google Scholar 

  9. Clarke R, van den Berg HW, Murphy RF (1990) Reduction of the membrane fluidity of human breast cancer cells by tamoxifen and 17 beta-estradiol. J Natl Cancer Inst 82:1702–5

    Article  PubMed  CAS  Google Scholar 

  10. Wiseman H: (1994) Tamoxifen: New membrane-mediated mechanisms of action and therapeutic advances. Trends Pharmacol Sci 15:83–9

    Article  PubMed  CAS  Google Scholar 

  11. Wiseman H, Quinn P (1994) The antioxidant action of synthetic oestrogens involves decreased membrane fluidity: Relevance to their potential use as anticancer and cardioprotective agents compared to tamoxifen? Free Radic Res 21:187–94

    Article  PubMed  CAS  Google Scholar 

  12. Wiseman H, Smith C, Halliwell B et al. (1992) Droloxifene (3-hydroxytamoxifen) has membrane antioxidant ability: Potential relevance to its mechanism of therapeutic action in breast cancer. Cancer Lett 66:61–8

    Article  PubMed  CAS  Google Scholar 

  13. Wiseman H (1994) Tamoxifen: Molecular Basis of Use in Cancer Treatment and Prevention. John Wiley & Sons, New York

    Google Scholar 

  14. Degani H, Furman E, Fields S (1994) Magnetic resonance imaging and spectroscopy of MCF7 human breast cancer: Pathophysiology and monitoring of treatment. Clin Chim Acta 228:19–33

    Article  PubMed  CAS  Google Scholar 

  15. Furman-Haran E, Margalit R, Maretzek AF, Degani H (1996) Angiogenic response of MCF7 human breast cancer to hormonal treatment: Assessment by dynamic GdDTPA-enhanced MRI at high spatial resolution. J Magn Reson Imaging 6:195–202

    Article  PubMed  CAS  Google Scholar 

  16. Gagliardi A, Collins DC (1993) Inhibition of angiogenesis by antiestrogens. Cancer Res 53:533–5

    PubMed  CAS  Google Scholar 

  17. Haran EF, Maretzek AF, Goldberg I et al. (1994) Tamoxifen enhances cell death in implanted MCF7 breast cancer by inhibiting endothelium growth. Cancer Res 54:5511–4

    PubMed  CAS  Google Scholar 

  18. Kelloff GJ, Boone CW, Steele VE et al. (1994) Mechanistic considerations in chemopreventive drug development. J Cell Biochem Suppl 20:1–24

    Article  PubMed  CAS  Google Scholar 

  19. Lindner DJ, Borden EC (1997) Effects of tamoxifen and interferon-beta or the combination on tumor-induced angiogenesis. Int J Cancer 71:456–61

    Article  PubMed  CAS  Google Scholar 

  20. McLeskey SW, Zhang L, Trock BJ et al. (1996) Effects of AGM-1470 and pentosan polysulphate on tumorigenicity and metastasis of FGF-transfected MCF-7 cells. Br J Cancer 73:1053–62

    PubMed  CAS  Google Scholar 

  21. Oehler MK, Hague S, Rees MC, Bicknell R (2002) Adrenomedullin promotes formation of xenografted endometrial tumors by stimulation of autocrine growth and angiogenesis. Oncogene 21:2815–21.

    Article  PubMed  CAS  Google Scholar 

  22. Thamrongwittawatpong L, Sirivatanauksorn Y, Batten JJ et al. (2001) The effect of N(G)-monomethyl-L-arginine and tamoxifen on nitric oxide production in breast cancer cells stimulated by oestrogen and progesterone. Euro J Surg 167:484–9

    Article  CAS  Google Scholar 

  23. Zhang HT, Craft P, Scott PA et al. (1995) Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J Natl Cancer Inst 87:213–9

    Article  PubMed  CAS  Google Scholar 

  24. Asahara T, Chen D, Takahashi T et al. (1998) Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ Res 83:233–40

    PubMed  CAS  Google Scholar 

  25. Ausprunk DH, Folkman J (1977) Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc Res 14:53–65

    Article  PubMed  CAS  Google Scholar 

  26. Ausprunk DH, Falterman K, Folkman J (1978) The sequence of events in the regression of corneal capillaries. Lab Invest 38:284–94

    PubMed  CAS  Google Scholar 

  27. Fournier GA, Lutty GA, Watt S et al. (1981) A corneal micropocket assay for angiogenesis in the rat eye. Invest Ophthalmol Vis Sci 21:351–4

    PubMed  CAS  Google Scholar 

  28. Gimbrone MAJ, Cotran RS, Leapman SB, Folkman J (1974) Tumor growth and neovascularization: An experimental model using the rabbit cornea. J Natl Cancer Inst 52: 413–27

    PubMed  Google Scholar 

  29. Kenyon BM, Voest EE, Chen CC et al. (1996) A model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci 37:1625–32

    PubMed  CAS  Google Scholar 

  30. Muthukkaruppan V, Auerbach R (1979) Angiogenesis in the mouse cornea. Science 205:1416–8

    Article  PubMed  CAS  Google Scholar 

  31. Polverini PJ, Bouck NP, Rastinejad F (1991) Assay and purification of naturally occurring inhibitor of angiogenesis. Methods Enzymol 198:440–50

    Article  PubMed  CAS  Google Scholar 

  32. Benelli U, Ross JR, Nardi M, Klintworth GK (1997) Corneal neovascularization induced by xenografts or chemical cautery. Inhibition by cyclosporin A. Invest Ophthalmol Vis Sci 38:274–82

    PubMed  CAS  Google Scholar 

  33. Jain RK, Schlenger K, Höckel M, Yuan F (1997) Quantitative angiogenesis assays: Progress and problems. Nat Med 3:1203–8

    Article  PubMed  CAS  Google Scholar 

  34. Li WW, Grayson G, Folkman J, D’Amore PA (1991) Sustained-release endotoxin. A model for inducing corneal neovascularization. Invest Ophthalmol Vis Sci 32:2906–11

    PubMed  CAS  Google Scholar 

  35. Conrad TJ, Chandler DB, Corless JM, Klintworth GK (1994) In vivo measurement of corneal angiogenesis with video data acquisition and computerized image analysis. Lab Invest 70:426–34

    PubMed  CAS  Google Scholar 

  36. Auerbach R, Arensman R, Kubai L, Folkman J (1975) Tumor-induced angiogenesis: Lack of inhibition by irradiation. Int J Cancer 15:241–5

    Article  PubMed  CAS  Google Scholar 

  37. Sierra-Honigmann MR, Nath AK, Murakami C et al. (1998) Biological action of leptin as an angiogenic factor. Science 281:1683–6

    Article  PubMed  CAS  Google Scholar 

  38. Proia AD, Chandler DB, Haynes WL et al. (1988) Quantitation of corneal neovascularization using computerized image analysis. Lab Invest 58:473–9

    PubMed  CAS  Google Scholar 

  39. Blackwell KL, Haroon ZA, Shan S et al. (2000) Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models. Clin Cancer Res 6:4359–64

    PubMed  CAS  Google Scholar 

  40. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Sem Oncol 29(6 Suppl 16):15–8

    CAS  Google Scholar 

  41. Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–39

    Article  PubMed  CAS  Google Scholar 

  42. Thackray BD, Nelson AC (1993) Semi-automatic segmentation of vascular network images using a rotating structuring element (ROSE) with mathematical morphology and dual feature thresholding. IEEE Trans Med Imaging 12:385–92

    Article  PubMed  CAS  Google Scholar 

  43. Sheng T, Yuan F (2001) Numerical simulations of angiogenesis in the cornea. Microvasc Res 61:14–27

    Article  Google Scholar 

  44. Lesclous P, Guez D, Llorens A, Saffar JL (2001) Time-course of mast cell accumulation in rat bone marrow after ovariectomy. Calcif Tissue Int 68:297–303

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Donald P.␣McDonnell for scientific discussion. The work supported in part by a grant from the Department of Defense (BC980191).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA

    Sheng Tong, Qing Chen & Fan Yuan

  2. Radiation Oncology, Duke University, Durham, North Carolina, USA

    Si-Qing Shan & Mark W. Dewhirst

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  1. Sheng Tong
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  2. Qing Chen
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  3. Si-Qing Shan
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  4. Mark W. Dewhirst
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  5. Fan Yuan
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Correspondence to Fan Yuan.

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Tong, S., Chen, Q., Shan, SQ. et al. Quantitative comparison of the inhibitory effects of GW5638 and tamoxifen on angiogenesis in the cornea pocket assay. Angiogenesis 9, 53–58 (2006). https://doi.org/10.1007/s10456-006-9029-x

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  • DOI: https://doi.org/10.1007/s10456-006-9029-x

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