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Basic Science Investigations |
1 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska
2 Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska
3 Corixa, South San Francisco, California
4 UCSF Cancer Center, University of California at San Francisco, San Francisco, California
Physiologic barriers to the delivery of macromolecules to solid tumors are a major obstacle to the clinical success of radioimmunotherapy (RIT). Only a small fraction of the injected dose of the radiolabeled monoclonal antibody (mAb) localizes at the tumor site. This situation worsens as the tumor burden increases. It is hypothesized that improvements to RIT of adenocarcinoma can be realized by inclusion of vasoactive agents, in particular agents able to increase the vascular permeability of tumor capillaries. In these studies, a response-selective peptide agonist of human C5a, GCGYSFKPMPLaR (AP), was used to transiently increase tumor vascular permeability in an effort to improve RIT of solid tumors. Methods: Athymic mice xenografted with human colorectal adenocarcinoma LS174T were treated intravenously with low doses (9.25 MBq) of 131I-labeled mAb B72.3 in combination with various intravenous doses of AP. The progression of the disease or the loss of >20% body weight was taken as the endpoint. Biodistribution and tumor uptake kinetics were studied in the same tumor-antibody system. Results: The uptake of 125I-B72.3 in LS174T xenografts increased in a dose-dependent manner with an apparent maximal effect between 3 and 6 h after intravenous administration of AP. Augmenting the dose of 9.25 MBq 131I-B72.3 with a single administration of 0.1 mg AP delayed tumor growth nearly 2-fold; the tumor quadrupling time (Tq) was 14.2 ± 3.3 d for 131I-B72.3 alone versus 26.0 ± 3.6 d for 131I-B72.3 plus 0.1 mg AP (P < 0.001). An additional dose of 0.1 mg AP 24 h after 131I-B72.3 further improved the therapeutic outcome (Tq = 48.5 ± 7.9 d; P < 0.001) and resulted in several cases of tumor regression. Conclusion: The inclusion of agonist peptides of human C5a in the RIT scheme results in improved tumor responses without any manifest side effects.
Key Words: radioimmunotherapy • vascular permeability • C5a agonist • tumor uptake • adenocarcinoma.
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