Enhancing cytotoxic agent activity in experimental pancreatic cancer through EMAP II combination therapy.
OBJECTIVE
Gemcitabine has limited benefits as single agent or in combination for pancreatic ductal adenocarcinoma (PDAC). Endothelial monocyte-activating polypeptide II (EMAP) enhances gemcitabine effects in PDAC. We evaluated the combination effects of EMAP, doxorubicin, and docetaxel in experimental PDAC.


METHODS
Cell proliferation, protein expression, and apoptosis were analyzed by WST-1 assay, Western blotting, and FACS analysis. Tumor growth and survival experiments were performed in murine xenografts.


RESULTS
PDAC cell proliferation in vitro was not affected by EMAP, compared to a small inhibition through doxorubicin, docetaxel, and gemcitabine. EMAP addition to these agents did not increase the antiproliferative effects. In endothelial cells, EMAP, doxorubicin, docetaxel, and gemcitabine all had antiproliferative effects. Addition of EMAP to these cytotoxic agents had additive effects. In PDAC cells, no agent induced measurable apoptosis, whereas in endothelial cells, all agents either alone or in combination did. Doxorubicin, docetaxel, gemcitabine, and EMAP all decreased tumor growth. EMAP addition increased inhibitory effects of docetaxel and gemcitabine, but not of doxorubicin. However, compared to controls (median survival: 17 days), EMAP (14 days) had no survival benefit, while docetaxel (29 days), gemcitabine (25 days), and docetaxel followed by gemcitabine sequence (37 days) extended animal survival. Addition of EMAP to docetaxel (35 days), gemcitabine (28 days), and docetaxel gemcitabine sequence (41 days) extended the survival. Doxorubicin effects were not enhanced by EMAP.


CONCLUSIONS
The antiendothelial combination therapy benefit through EMAP is not limited to gemcitabine and may facilitate the development of more effective alternative cytotoxic therapy strategies against PDAC.
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-8548, USA.
Niranjan
N
Awasthi
Margaret A
MA
Schwarz
Roderich E
RE
Schwarz
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000627:therapeutic use*; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D016601:RNA-Binding Proteins / Q000627:therapeutic use*; D016019:Survival Analysis; D043823:Taxoids / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C110656:2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D043823:Taxoids; D013778:Tetrazolium Salts; C077219:small inducible cytokine subfamily E, member 1; D000077143:Docetaxel; D004317:Doxorubicin