Anti-vascular effects of vinflunine in the MAC 15A transplantable adenocarcinoma model.
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.
Holwell
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SE
Clinical Oncology Unit, University of Bradford, West Yorkshire, BD7 1DP, UK.
Hill
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BT
Bibby
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MC
D000230:Adenocarcinoma / Q000473:pathology / Q000517:prevention & control*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology; D000077235:Vinorelbine
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; C111217:vinflunine; D014750:Vincristine; D014747:Vinblastine; D000077235:Vinorelbine