Oxi4503, a novel vascular targeting agent: effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate.
Oxi4503, which is the diphosphate prodrug of combretastatin A1, is a novel vascular targeting agent from the combretastatin family. Another member of this family, Combretastatin A-4 phosphate (CA4P), is a well-characterized vascular targeting agent already being evaluated in clinical trials. The potential for tumor vascular targeting by Oxi4503 was assessed in a mouse system. This approach aims to shut down the established tumor vasculature, leading to the development of extensive tumor cell necrosis. The vascular effects of Oxi4503 were assessed in the s.c. implanted MDA-MB-231 adenocarcinoma and the MHEC5-T hemangio-endothelioma in SCID mice and in a range of normal tissues. Blood flow was measured by i.v. injection of fluorescence beads, while quantitative fluorescence microscopy was used to measure the spatial heterogeneity of blood flow in tumor sections. Oxi4503 induced the shutdown of tumor blood vessels in a dose-dependent pattern with an ED50 at 3 mg/kg in contrast to 43 mg/kg of CA4P. Quantitative fluorescence microscopy showed that Oxi4503 increased the spatial heterogeneity in tumor blood flow. Oxi4503 affected peripheral tumor regions less than central regions, although this was not as pronounced as seen with CA4P, where only central regions were affected. The vascular shutdown induced by administration of Oxi4503 at a dose of 6 mg/kg resulted in extensive cell loss 24 hours following treatment, which translated into a significant effect on tumor growth. Tumor growth was completely repressed at doses above 12.5 mg/kg of Oxi4503, while doses above 25 mg/kg showed tumor regression and even complete regression in some animals. These results are promising for the use of Oxi4503 as a tumor vascular targeting agent. Moreover the potent antitumor effect when administered as a single agent suggests a different activity profile than CA4P.
Hua
Jianyi
J
Department of Cell and Molecular Biology, Section for Tumor Immunology, University of Lund, BMC: 112, 22184 Lund, Sweden. Jianyi.Hua@wblab.lu.se
Sheng
Yezhou
Y
Pinney
Kevin G
KG
Garner
Charles M
CM
Kane
Robert R
RR
Prezioso
Joseph A
JA
Pettit
George R
GR
Chaplin
David J
DJ
Edvardsen
Klaus
K
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D011756:Diphosphates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005456:Fluorescent Dyes / Q000032:analysis / Q000493:pharmacokinetics; D006390:Hemangioendothelioma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008863:Microspheres; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D012039:Regional Blood Flow; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D011756:Diphosphates; D005456:Fluorescent Dyes; C465018:Oxi 4503; D013267:Stilbenes; C058728:fosbretabulin