Combined treatment of L1CAM antibodies and cytostatic drugs improve the therapeutic response of pancreatic and ovarian carcinoma.
The adhesion molecule L1CAM (CD171) accounts for enhanced motility, invasiveness and chemoresistance of tumor cells and represents a novel marker for various tumor entities including pancreatic and ovarian carcinoma. Recently, we showed that L1CAM inhibition increases the apoptotic response of tumor cells towards cytostatic drugs pointing to the potential of L1CAM to serve as a chemosensitizer in anti-cancer therapy. Thus, the present study evaluated the therapeutic potential of combined treatment with L1CAM antibodies and chemotherapeutic drugs in pancreatic and ovarian carcinoma model systems in vivo. Two L1CAM-specific antibodies (L1-14.10 and L1-9.3/2a) exhibiting high binding affinity to the L1CAM expressing pancreatic adenocarcinoma cell line Colo357 and the ovarian carcinoma cell line SKOV3ip were used for treatment. The combined therapy of SCID mice with either L1CAM antibody and gemcitabine and paclitaxel, respectively, reduced the growth of subcutaneously grown Colo357 or SKOV3ip tumors more efficiently than treatment with the cytostatic drug alone or in combination with control IgG. This was accompanied by an increased number of apoptotic tumor cells along with an elevated procaspase-8 expression. Furthermore, a lowered activation of NF-κB along with a reduced expression of VEGF and a diminished number of CD31-positive blood vessels were observed in tumors after combined therapy compared to control treatments, while the infiltration of F4/80-positive macrophages increased. Overall, these data provide new insights into the mechanism of the anti-cancer activity of L1CAM-blocking antibodies in vivo and support the suitability of L1CAM as a target for chemosensitization and of L1CAM-interfering antibodies as an appropriate tool to increase the therapeutic response of pancreatic and ovarian carcinoma.
Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany.
Heiner
H
Schäfer
Chantal
C
Dieckmann
Olena
O
Korniienko
Gerhard
G
Moldenhauer
Helena
H
Kiefel
Alexey
A
Salnikov
Achim
A
Krüger
Peter
P
Altevogt
Susanne
S
Sebens
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D002277:Carcinoma / Q000188:drug therapy*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D016513:Mice, SCID; D039842:Neural Cell Adhesion Molecule L1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D054697:Cytostatic Agents; D039842:Neural Cell Adhesion Molecule L1; D003841:Deoxycytidine; D017239:Paclitaxel; D000093542:Gemcitabine