Abstract
Combretastatin-A4 phosphate (cis -CA-4) is a tubulin-binding agent currently undergoing clinical trials as an anti-tumour drug. We have investigated whether CA-4 functions as a tumour-specific anti-vascular agent using the hyperplastic thyroid as a novel in vivo model of neovascularization. CA-4 elicited pathological changes in normal tissue, manifested as the induction of multiple, discrete intravascular thrombi. These vascular-damaging effects indicate that CA-4P does not function as a tumour-specific agent but targets neovasculature irrespective of the primary angiogenic stimulus. © 2001 Cancer Research Campaign
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References
Beauregard DA, Thelwall PE, Chaplin DJ, Hill SA, Adams GE and Brindle KM (1998) Magnetic resonance imaging and spectroscopy of combretastatin A(4) prodrug-induced disruption of tumour perfusion and energetic status. Br J Cancer 77: 1761–1767
Bedford SB, Quarterman CP, Rathbone DL, Slack JA, Griffin RJ and Stevens MFG (1996) Synthesis of water-soluble prodrugs of the cytotoxic agent combretastatin A4. Bio Med Chem Lett 6: 157–160
Bidey SP, Hill DJ and Eggo MC (1999) Growth factors and goitrogenesis. J Endocrinol 160: 321–332
Dark GG, Hill SA, Prise VE, Tozer GM, Pettit GR and Chaplin DJ (1997) Combretastatin A-4, an agent that displays potent and selective toxicity toward tumour vasculature. Cancer Res 57: 1829–1834
Griggs J, Metcalfe JC and Hesketh R (2001) Targeting tumour vasculature: the development of Combretastatin A4. The Lancet Oncology 2: 82–87
Grosios K, Holwell SE, McGown AT, Pettit GR and Bibby MC (1999) In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug. Br J Cancer 81: 1318–1327
Hanahan D and Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364
Hayes AJ, Li LY and Lippman ME (2000) Anti-vascular therapy: a new approach to cancer treatment. Western J Med 172: 39–42
Orsini F, Pelizzoni F, Bellini B and Miglierini G (1997) Synthesis of biologically active polyphenolic glycosides (combretastatin and resveratrol series). Carbohydrate Res 301: 95–109
Peter H, Gerber H, Studer H, Groscurth P and Zakarija M (1991) Comparison of FRTL-5 cell growth in vitro with that of xenotransplanted cells and the thyroid of the recipient mouse. Endocrinology 128: 211–219
Pettit GR and Rhodes MR (1998) Antineoplastic agents 389. New syntheses of the combretastatin A-4 prodrug. Anti-Cancer Drug Design 13: 183–191
Pettit GR, Singh SB, Boyd MR, Hamel E, Pettit RK, Schmidt JM and Hogan F (1995) Antineoplastic agents 291. Isolation and synthesis of combretastatins a-4, a-5, and a-6. J Med Chem 38: 1666–1672
Pettit GR, Rhodes MR, Herald DL, Chaplin DJ, Stratford MRL, Hamel E, Pettit RK, Chapuis JC and Oliva D (1998) Antineoplastic agents 393. Synthesis of the trans -isomer of combretastatin A-4 prodrug. Anti-Cancer Drug Design 13: 981–993
Sato K, Yamazaki K, Shizume KYK, Obara T, Ohsumi K, Demura H, Yamaguchi S and Shibuya M (1995) Stimulation by thyroid-stimulating hormone and Graves’ immunoglobulin G of vascular endothelial growth factor mRNA expression in human follicles in vitro and flt mRNA expression in the rat thyroid in vivo. J Clin Investigation 96: 1295–1302
Tozer GM, Prise VE, Wilson J, Locke RJ, Vojnovic B, Stratford MRL, Dennis MF and Chaplin DJ (1999) Combretastatin A-4 phosphate as a tumour vascular-targeting agent: Early effects in tumours and normal tissues. Cancer Res 59: 1626–1634
Viglietto G, Romano A, Manzo G, Chiappetta G, Paoletti I, Califano D, Galati M, Mauriello V, Bruni P, Laog C, Fusco A and Persico M (1997) Upregulation of the angiogenic factors PIGF, VEGF and their receptors (Flt-1, Flk-1/KDR) by TSH in cultured thyrocytes and in the thyroid gland of thiouracil-fed rats suggests a TSH-dependent paracrine mechanism for goitre hypervascularisation. Oncogene 15: 2687–2698
Wang J, Milosveski V, Schramek C, Fong G, Becks G and Hill D (1998) Presence and possible role of vascular endothelial growth factor in thyroid cell growth and function. J Endocrinol 157: 5–12
Wynford-Thomas D, Stringer B and Williams ED (1982a) Dissociation of growth and function in the rat thyroid during prolonged goitrogen administration. Acta Endocrinol 101: 210–216
Wynford-Thomas D, Stringer B and Williams ED (1982b) Goitrogen induced thyroid growth in the rat: a quantitative morphometric study. Acta Endocrinol 94: 131–140
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Griggs, J., Hesketh, R., Smith, G. et al. Combretastatin-A4 disrupts neovascular development in non-neoplastic tissue. Br J Cancer 84, 832–835 (2001). https://doi.org/10.1054/bjoc.2000.1653
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DOI: https://doi.org/10.1054/bjoc.2000.1653
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