Abstract
Anti-vascular effects of the novel Vinca alkaloid, vinflunine have been investigated in the MAC 15A transplantable murine colon adenocarcinoma model and compared with those induced by the most recently identified clinically useful third generation Vinca. Administration of the maximum tolerated dose of either vinflunine (50 mg kg–1) or vinorelbine (8 mg kg–1) resulted in significant tumour growth delay with subsequent histological analysis revealing substantial haemorrhagic necrosis. This suggested possible anti-vascular effects and these were confirmed by Hoechst 33342 perfusion studies. Vinflunine, currently undergoing Phase I trials in Europe, was found to be at least as effective as the clinically active vincristine and vinorelbine in this model and, remarkably, produced anti-vascular effects at doses much lower than the maximum tolerated dose. Although vinflunine caused apoptosis in HUVEC monolayer cultures this event did not occur within the first 8 hours of exposure whereas vascular shutdown in vivo was observed within the first 4 hours. © 2001 Cancer Research Campaign http://www.bjcancer.com
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References
Algire GH, Legallais FY and Anderson BF (1954) Vascular reactions of normal and malignant tissues in vivo. VI. The role of hypotension in the action of components of podophyllin on transplanted sarcomas. J Natl Cancer Inst 14: 879–887
Baguley BC, Holdaway KH, Thomsen LL, Zhuang L and Zwi LJ (1991) Inhibition of growth of colon 38 adenocarcinoma by vinblastine and colchicine. Evidence for a vascular mechanism. Eur J Cancer 27: 482–487
Berthaud P, Le Chevalier T, Ruffie P, Baldeyrou P, Arriagada R, Besson F and Tursz T (1992) Phase I–II study of vinorelbine (Navelbine) plus cisplatin in advanced non-small cell lung cancer. Eur J Cancer 28: 1863–1865
Budman DR (1992) New vinca alkaloids and related compounds. Semin Oncol 19: 639–645
Budman DR (1997) Vinorelbine (Navelbine): a third-generation Vinca alkaloid. Cancer Invest 15: 475–490
Chaplin DJ and Dougherty GJ (1999) Tumour vasculature as a target to cancer therapy. Br J Cancer 80: 57–64
Cowen SE, Bibby MC and Double JA (1995) Characterisation of the vasculature within a murine adenocarcinoma growing in different sites to evaluate the potential of vascular therapies. Acta Oncol 34: 357–360
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
Fahy J, Duflos A, Ribet JP, Jacquesy JC, Berrier C, Jouannetaud MP and Zunino F (1997) Vinca alkaloids in superacid media: a method for creating a new family of antitumor derivatives. J Am Chem Soc 119: 8576–8577
Fumoleau P, Delgado FM, Delozier T, Monnier A, Gil Delgado MA, Kerbrat P, Garcia-Giralt, Keiking R, Namer M, Closon MT, Goudier MJ, Chollet P, Lecourt L and Montcuquet P (1993) Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol 11: 1245–1252
Fumoleau P, Delozier T, Extra JM, Canobbio L, Delgado FM and Hurteloup P (1995) Vinorelbine (Navelbine) in the treatment of breast cancer: the European experience. Semin Oncol 22 [2 suppl 5]: 22–29
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
Hayes AJ, Li LY and Lippman ME (1999) Antivascular therapy: a new approach to cancer treatment. BMJ 318: 853–856
Hill SA, Longergan SJ, Denekamp J and Chaplin DJ (1993) Vinca alkaloids: anti-vascular effects in a murine tumour. Eur J Cancer 29: 1320–1324
Hill BT, Fiebig HH, Waud WR, Poupon MF, Colpaert F and Kruczynski A (1999) Superior in vivo experimental antitumour activity of vinflunine, relative to vinorelbine, in a panel of human tumour xenografts. Eur J Cancer 35: 512–520
Johnson SA, Harper P, Hortobagyi GN and Pouillart P (1996) Vinorelbine: an overview. Cancer Treat Rev 22: 127–142
Kruczynski A, Colpaert F, Tarayre JP, Mouillard P, Fahy J and Hill BT (1998a) Preclinical in vivo antitumour activity of vinflunine, a novel fluorinated Vinca alkaloid. Cancer Chemother Pharmacol 41: 437–447
Kruczynski A, Barret J-M, Etievant C, Colpaert F, Fahy J and Hill BT (1998b) Anti-mitotic and tubulin-interactive properties of vinflunine, a novel fluorinated vinca alkaloid. Biochem Pharmacol 55: 635–648
Laws AL, Matthew AM, Double JA and Bibby MC (1995) Preclinical in vitro and in vivo activity of 5,6-dimethylxanthenone-4-acetic acid. Br J Cancer 71: 1204–1209
Le Chevalier T, Brisgand D, Douillard JY, Pujol JL, Alberola V, Monnier A, Riviere A, Lianes P, Chomy P, Cigolari S, Gottfried M, Ruffie P, Panizo A, Gaspard MH, Ravaioli A, Besenval M, Besson F, Martinez A, Berthaud P and Tursz T (1994) Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol 12: 360–367
Ludford RJ (1948) Factors determining the action of colchicine on tumour growth. Br J Cancer 2: 75–86
Phillips RM, Bibby MC and Double JA (1988) Experimental correlations of in vitro drug sensitivity with in vivo responses to Thio TEPA in a panel of murine: tumours. Cancer Chemother Pharmacol 21: 168–172
Quinn PK, Bibby MC, Cox JA and Crawford SM (1992) The influence of hydralazine on the vasculature, blood perfusion and chemosensitivity of MAC tumours. Br J Cancer 66: 323–330
Romero A, Rabinovich MG and Vallejo CT (1994) Vinorelbine as first-line chemotherapy for metastatic breast cancer. J Clin Oncol 12: 336–341
Tozer GM, Prise VE, Wilson J, Locke RJ, Vojnovic B, Stratford MRL, Dennis MF and Chaplin DJ (1999) Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues. Cancer Res 59: 1626–1634
UKCCCR Guidelines for the Welfare of Animals in Experimental Neoplasia (1998) Br J Cancer 77: 1–10
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Holwell, S., Hill, B. & Bibby, M. Anti-vascular effects of vinflunine in the MAC 15A transplantable adenocarcinoma model. Br J Cancer 84, 290–295 (2001). https://doi.org/10.1054/bjoc.2000.1587
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DOI: https://doi.org/10.1054/bjoc.2000.1587
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