Effect of vascular targeting agent Oxi4503 on tumor cell kinetics in a mouse model of colorectal liver metastasis.
BACKGROUND
Oxi4503 has been shown to inhibit tumor growth and improve survival in an animal model of colorectal (CRC) liver metastases. This agent appears to selectively target the endothelial cytoskeleton with resultant vessel occlusion and tumor necrosis.


METHODS
This study evaluated the pattern of tumor necrosis caused by Oxi4503, with particular emphasis on patterns of cell proliferation and apoptosis in a murine model of CRC liver metastases.


RESULTS
A single dose of Oxi4503 caused immediate tumor vasculature collapse and subsequently tumor necrosis. There was widespread central necrosis with evidence of viable tumor cells at the periphery. Alterations in the number and spatial pattern of tumor cells undergoing apoptosis and the rate of cellular proliferation were also observed following treatment. Microvessel density was reduced following treatment, however patent vessels were still observed within the necrotic core.


CONCLUSIONS
Although Oxi4503 caused significant tumor destruction, synergistic treatment with cytotoxic and/or anti-angiogenic agents should be considered in order to achieve complete tumor eradication and long-term survival.
Chan
Lie Sam
LS
University of Melbourne, Department of Surgery, Austin Hospital, Heidelberg, Victoria 3084, Australia. l.chan11@pgrad.unimelb.edu.au
Malcontenti-Wilson
Cathy
C
Muralidharan
Vijayaragavan
V
Christophi
Christopher
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011756:Diphosphates / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D013267:Stilbenes / Q000494:pharmacology* / Q000633:toxicity
D011756:Diphosphates; C465018:Oxi 4503; D013267:Stilbenes