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Effect of Molecular Therapeutics on Liver Regeneration in a Murine Model

George Van Buren, II, Anthony D. Yang, Nikolaos A. Dallas, Michael J. Gray, Sherry J. Lim, Ling Xia, Fan Fan, Ray Somcio, Yan Wu, Daniel J. Hicklin, Lee M. Ellis

From the Departments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ImClone Systems Inc, New York, NY

Corresponding author: Lee M. Ellis, MD, Department of Surgical Oncology, Unit 444, The University of Texas M.D. Anderson Cancer Center, PO Box 301402, Houston, TX 77230-1402; e-mail: lellis{at}mdanderson.org

Purpose Unresectable metastatic colorectal cancer (CRC) can be rendered resectable with systemic chemotherapy in approximately 20% of cases. Most patients with metastatic CRC receive chemotherapy with the addition of targeted therapy with anti–vascular endothelial growth factor (VEGF) or anti–epidermal growth factor receptor (EGFR) antibodies. We sought to determine whether anti-VEGF receptor (VEGFR) or anti-EGFR therapy would impair liver regeneration after partial hepatectomy (PH) in mice.

Materials and Methods Mice underwent either 66% PH or sham laparotomy. In the first experiment, mice in the PH group were randomly assigned to receive daily intraperitoneal injections of monoclonal antibodies (MoABs) to murine VEGFR-2 or nonspecific MoABs (control). In the second experiment, mice in the PH group were randomly assigned to receive intraperitoneal injections of antimurine EGFR or nonspecific (control) MoABs. In both experiments, therapy was initiated the day before surgery and continued until the mice were killed on day 5. Livers were collected and processed.

Results Anti–VEGFR-2 therapy slightly impaired liver regeneration and hepatic cell proliferation compared with control. Hematoxylin and eosin staining showed no differences in liver morphology. CD105 staining showed decreased levels of activated endothelium in livers in the VEGFR-2 MoAB group. VEGFR-2 MoAB therapy decreased the levels of the cell cycle regulators cyclin D1 and cyclin D3 and the regenerative cytokine interleukin-6. Anti-EGFR therapy had no effect on liver regeneration or cellular proliferation.

Conclusion Anti–VEGFR-2 therapy slightly impaired liver regeneration in this murine model, whereas anti-EGFR therapy had no effect on liver regeneration.

Supported by National Institutes of Health Grants No. T-32 09599 (G.V.B., A.D.Y., N.A.D., and S.J.L.) and ImClone Systems (Y.W., D.J.H., and L.M.E.).

Both G.V.B. II and A.D.Y. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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