Effect of molecular therapeutics on liver regeneration in a murine model.
OBJECTIVE
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.


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.


CONCLUSIONS
Anti-VEGFR-2 therapy slightly impaired liver regeneration in this murine model, whereas anti-EGFR therapy had no effect on liver regeneration.
Van Buren
George
G
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, PO Box 301402, Houston, TX 77230-1402, USA.
Yang
Anthony D
AD
Dallas
Nikolaos A
NA
Gray
Michael J
MJ
Lim
Sherry J
SJ
Xia
Ling
L
Fan
Fan
F
Somcio
Ray
R
Wu
Yan
Y
Hicklin
Daniel J
DJ
Ellis
Lee M
LM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D006498:Hepatectomy; D007274:Injections, Intraperitoneal; D008099:Liver / Q000473:pathology*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011897:Random Allocation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology
D000911:Antibodies, Monoclonal; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors