Matuzumab short-term therapy in experimental pancreatic cancer: prolonged antitumor activity in combination with gemcitabine.
OBJECTIVE
The epidermal growth factor receptor ErbB-1 is commonly expressed in pancreatic cancer and ErbB-1 targeting has shown promising results. We wanted to evaluate matuzumab (EMD72000), a fully humanized ErbB-1-specific monoclonal antibody in combination with gemcitabine in experimental pancreatic cancer.


METHODS
Using the human pancreatic cancer cell line L3.6pl, we investigated matuzumab in vitro and in vivo. ErbB-1 phosphorylation and downstream pathway activation were evaluated by Western blot. Proliferation and migration assays and fluorescence-activated cell sorting analysis were done. For in vivo studies, we used an orthotopic nude mice model in which 40 mg/kg of matuzumab+/-100 mg/kg of gemcitabine were administered twice weekly. Different treatment durations (7, 14, 21, and 25 days) and varying time points of treatment initiation (days 8, 15, 22, and 29) were evaluated. Ki67, CD31, and phosphorylated p44/42 mitogen-activated protein kinase (MAPK) immunohistochemistry were done.


RESULTS
ErbB-1 phosphorylation and downstream MAPK and AKT signaling were significantly reduced by matuzumab. Matuzumab significantly inhibited proliferation and migration in vitro, and induced tumor cell apoptosis in a dose-dependant manner. Matuzumab therapy significantly lowered tumor volume in vivo, reduced lymph node and liver metastases, and decreased microvessel density and tumor cell proliferation. These effects were significantly enhanced when gemcitabine was added. A significant and prolonged antitumor activity was even evident with short-term therapy (7 days) and with a late onset of therapy (day 22 after tumor cell injection).


CONCLUSIONS
Matuzumab is an effective agent with long-lasting antiproliferative, proapoptotic, antiangiogenic, and antimetastatic activity in human pancreatic cancer models. These effects might be potentiated by gemcitabine.
Kleespies
Axel
A
Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilian-University, Munich, Germany. axelkleespies@aol.com
Ischenko
Ivan
I
Eichhorn
Martin E
ME
Seeliger
Hendrik
H
Amendt
Christiane
C
Mantell
Ole
O
Jauch
Karl-Walter
KW
Bruns
Christiane J
CJ