Preclinical evaluation of vascular-disrupting agents in Ewing's sarcoma family of tumours.
The effects of the tubulin-binding vascular-disrupting agents (VDAs), combretastatin A4 phosphate (CA4P), OXi4503/CA1P and OXi8007, in subcutaneous mouse models of the Ewing's sarcoma family of tumours (ESFTs) have been investigated alone and in combination with doxorubicin. Delay in subcutaneous tumour growth was observed following treatment of mice with multiple doses of OXi4503/CA1P but not with CA4P or OXi8007. A single dose of OXi4503/CA1P caused complete shutdown of vasculature by 24h and extensive haemorrhagic necrosis by 48h. However, a viable rim of proliferating cells remained, which repopulated the tumour within 10 days following the withdrawal of treatment. Combined treatment with doxorubicin 1h prior to administration of OXi4503/CA1P enhanced the effects of OXi4503/CA1P causing a synergistic delay in tumour growth (p<0.001). This study demonstrates that OXi4503/CA1P is a potent VDA in ESFT and in combination with conventional cytotoxic agents represents a promising treatment strategy for this tumour group.
Dalal
Surita
S
Candlelighter's Children's Cancer Research Group, Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, St. James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. s.dalal@leeds.ac.uk
Burchill
Susan A
SA
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001632:Bibenzyls / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D011756:Diphosphates / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D012512:Sarcoma, Ewing / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D013267:Stilbenes / Q000008:administration & dosage / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D011756:Diphosphates; C465018:Oxi 4503; D013267:Stilbenes; C040105:combretastatin; D004317:Doxorubicin; C058728:fosbretabulin