Matuzumab Short-Term Therapy in Experimental Pancreatic Cancer: Prolonged Antitumor Activity in Combination with Gemcitabine

• Published in: Clinical cancer research Vol. 14; no. 17; pp. 5426 - 5436
• Main Authors: KLEESPIES, Axel, ISCHENKO, Ivan, EICHHORN, Martin E, SEELIGER, Hendrik, AMENDT, Christiane, MANTELL, Ole, JAUCH, Karl-Walter, BRUNS, Christiane J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2008
• Subjects: AKT; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Cell Movement - drug effects; Cell Proliferation - drug effects; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; EGFR; EMD72000; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; MAPK; Medical sciences; Mice; monoclonal antibody; Neoplasm Metastasis - prevention & control; Neovascularization, Pathologic - drug therapy; Pancreatic Neoplasms - drug therapy; Pharmacology. Drug treatments; targeted therapy; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Antineoplastic agent; Short term; Drug combination; Gemcitabine; Monoclonal antibody; Malignant tumor; Biological activity; Matuzumab; Treatment; Antimetabolic; Pancreas cancer; Pyrimidine derivatives; Digestive diseases; Fluorine Organic compounds; Pyrimidine nucleoside; Cancer; Pancreatic disease; Prolonged
• DOI: 10.1158/1078-0432.CCR-07-5245
• ISSN: 1078-0432

Purpose: 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. Experimental Design: 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.