Synergy between vascular targeting agents and antibody-directed therapy.
OBJECTIVE
Tumor heterogeneity necessitates the use of combined therapies. We have shown that combining antibody-directed therapy with antivascular agents converts a subcurative to a curative treatment. The purpose of this study was to investigate, by radioluminographic and microscopic techniques, the regional effects of the two complementary therapies.


METHODS
Nude mice bearing colorectal tumors were injected with 125I-labeled anti-carcinoembryonic antigen antibody, and images were obtained for antibody distribution and modeling studies using radioluminography. For therapy studies, the mice were given radioimmunotherapy alone (131I-A5B7 anti-carcinoembryonic antigen antibody), the antivascular agent combretastatin A-4 3-0-phosphate (200 mg/kg), or both. Extra mice were used to study the regional tumor effects of these therapies over time: relevant histochemical procedures were performed on tissue sections to obtain composite digital microscopic images of apoptosis, blood vessels, perfusion, hypoxia, and morphology.


RESULTS
Antibody distribution, modeling, and immunohistochemistry showed how radioimmunotherapy (7.4 MBq/40 microg antibody) effectively treated the outer, well-oxygenated tumor region only. Combretastatin A-4 3-0-phosphate treated the more hypoxic center, and in doing so altered the relationship between tumor parameters.


CONCLUSIONS
The combined complementary therapies produced cures by destroying tumor regions with different pathophysiologies. Relating these regional therapeutic effects to the relevant tumor parameters microscopically allows optimization of therapy and improved translation to clinical trials.
Pedley
R Barbara
RB
Department of Oncology, Cancer Research UK Targeting and Imaging Group, Royal Free and University College Medical School, England, London, UK. r.b.pedley@ucl.ac.uk
El-Emir
Ethaar
E
Flynn
Aiden A
AA
Boxer
Geoffrey M
GM
Dearling
Jason
J
Raleigh
James A
JA
Hill
Sally A
SA
Stuart
Sam
S
Motha
Reeya
R
Begent
Richard H J
RH
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003131:Combined Modality Therapy; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic; D016499:Radioimmunotherapy; D013997:Time Factors; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D007074:Immunoglobulin G