Combination of a monoclonal anti-phosphatidylserine antibody with gemcitabine strongly inhibits the growth and metastasis of orthotopic pancreatic tumors in mice.
Pancreatic cancer continues to have a dismal prognosis and novel therapy is needed. In this study, we evaluate a promising new target for therapy, phosphatidylserine (PS). PS is an anionic phospholipid located normally on the inner leaflet of the plasma membrane in mammalian cells. In the tumor microenvironment, PS becomes externalized on vascular endothelium. The monoclonal antibody 3G4 binds PS and promotes an inflammatory response against tumor blood vessels, resulting in reduction of tumor growth. Mice with orthotopic pancreatic tumors were treated with 3G4, gemcitabine or a combination of both drugs. Tumor burden including pancreas weight and metastatic lesions (liver, lymph node and peritoneal) were reduced 3- to 5-fold by the combination therapy as compared with 1.5- to 2-fold with 3G4 and gemcitabine alone, respectively. Treatment of tumor-bearing animals with the combination therapy increased macrophage infiltration into the tumor mass 10-fold and reduced microvessel density in the tumor by 2.5-fold compared with tumors from untreated animals. Gemcitabine alone and 3G4 alone were less effective than the combination of the 2 agents together. The additive therapeutic effect of both agents appears to be because chemotherapy increases PS exposure on tumor vascular endothelium and amplifies the target for attack by 3G4. In conclusion, 3G4 enhanced the anti-tumor and anti-metastatic activity of gemcitabine without contributing to toxicity.
Beck
Adam W
AW
Simmons Comprehensive Cancer Center and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
Luster
Troy A
TA
Miller
Andrew F
AF
Holloway
Shane E
SE
Conner
Chris R
CR
Barnett
Carlton C
CC
Thorpe
Philip E
PE
Fleming
Jason B
JB
Brekken
Rolf A
RA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010718:Phosphatidylserines / Q000276:immunology* / Q000502:physiology; D014183:Transplantation, Heterologous; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D010718:Phosphatidylserines; D003841:Deoxycytidine; D000093542:Gemcitabine