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Combined treatment of L1CAM antibodies and cytostatic drugs improve the therapeutic response of pancreatic and ovarian carcinoma 10.1016/j.canlet.2011.12.035 : Cancer Letters | ScienceDirect.com
Abstract
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 (severe combined immunodeficiency) 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.Abbreviations
- IgG, immunoglobulin G;
- mAb, monoclonal antibody;
- MRP, multidrug resistance protein;
- PDAC, pancreatic ductal adenocarcinoma;
- SCID, severe combined immunodeficiency;
- SD, standard deviation;
- TUNEL, TdT-mediated dUTP nick end labelling;
- VEGF, Vascular Endothelial Growth Factor
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