In vivo videomicroscopy reveals differential effects of the vascular-targeting

Authors: Hemanth Varghese¹; Lisa Mackenzie²; Alan Groom³; Christopher Ellis³; Anderson Ryan⁴; Ian Macdonald⁵; Ann Chambers⁶

Source: Angiogenesis, Volume 7, Number 2, 2004 , pp. 157-164(8)

Publisher: Springer

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Abstract:

Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on vascular development and function within metastases were compared in an experimental liver metastasis model. Ras-transformed PAP2 fibroblasts were injected into the mesenteric veins of SCID mice to produce a control liver metastasis burden of sim

40% at 14 days. Mice given a single dose of ZD6126 (200 mg/kg, i.p.) on day 13 were examined 24 h later. Histology revealed a significant reduction in metastatic burden, associated with extensive tumor necrosis, increased tumor cell apoptosis and a reduction in tumor-associated vasculature. In vivo videomicroscopy (IVVM) revealed disrupted, non-functional vascular channels within metastases, with no blood flow. Mice given ZD6474 on days 4 to 10 (50 mg/kg daily, oral gavage) were examined on day 11. Histology revealed a lower metastatic burden, significant reductions in metastasis size and vasculature, and a significant increase in tumor cell apoptosis. IVVM revealed extensive reductions in vascularity and blood flow within metastases. Neither ZD6126 nor ZD6474 treatment affected surrounding normal liver tissue. This study shows that both agents can reduce experimental liver metastasis with no apparent effect on normal vasculature. However, these reductions were attained through distinct effects on the metastatic vasculature. Understanding differences in the modes of action of VTAs and anti-angiogenic agents will be important in optimizing their clinical application and in developing appropriate combination strategies.

Keywords: anti-angiogenesis; vascular-targeting; VEGF; ZD6126; ZD6474

Document Type: Research article

DOI: http://dx.doi.org/10.1007/s10456-004-1941-3

Affiliations: 1: Department of Medical Biophysics, University of Western Ontario, Canada; London Regional Cancer Centre, Canada 2: London Regional Cancer Centre, Canada 3: Department of Medical Biophysics, University of Western Ontario, Canada 4: Cancer and Infection Bioscience Department, Cheshire, UK 5: Department of Medical Biophysics, University of Western Ontario, Canada; Department of Oncology, University of Western Ontario, Canada 6: Department of Medical Biophysics, University of Western Ontario, Canada; London Regional Cancer Centre, Canada; Department of Oncology, University of Western Ontario, Canada

Publication date: 2004-01-01

In vivo videomicroscopy reveals differential effects of the vascular-targeting

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