TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth.
OBJECTIVE
To evaluate agonistic TRA-8 monoclonal antibody to human death receptor 5 (DR5) and gemcitabine in vitro and in an orthotopic pancreatic cancer model.


METHODS
Pancreatic cancer cell lines were screened for DR5 expression, cytotoxicity, and apoptosis induced by TRA-8, gemcitabine, or gemcitabine and TRA-8. An orthotopic model of pancreatic cancer was established in severe combined immunodeficient mice. Mice were treated with TRA-8, gemcitabine, or a combination for one or two cycles of therapy. Tumor growth (ultrasound) and survival were analyzed.


RESULTS
All five pancreatic cancer cell lines showed DR5 protein expression and varying sensitivity to TRA-8-mediated cytotoxicity. MIA PaCa-2 cells were very sensitive to TRA-8, moderately resistant to gemcitabine, with additive cytotoxicity to the combination. S2-VP10 cells were resistant to TRA-8 and sensitive to gemcitabine with synergistic sensitivity to the combination. Combination treatment in vitro produced enhanced caspase-3 and caspase-8 activation. A single cycle of therapy produced comparable efficacy for single-agent TRA-8 and the combination of TRA-8 and gemcitabine, with significant reduction in tumor size and prolonged survival compared with gemcitabine alone or control animals. With two cycles of therapy, TRA-8 and combination therapy produced enhanced inhibition of tumor growth compared with single-agent gemcitabine or untreated animals. However, the combination regimen showed enhanced survival as compared with single-agent TRA-8.


CONCLUSIONS
Pancreatic cancer cell lines express varying levels of DR5 and differ in their sensitivity to TRA-8 and gemcitabine-induced cytotoxicity. TRA-8 with two cycles of gemcitabine therapy produced the best overall survival.
Derosier
Leo Christopher
LC
Departments of Surgery, University of Alabama at Birmingham, 1530 3rd Avenue South, Wallace Tumor Institute 674, Birmingham, AL 35294-6832, USA.
Vickers
Selwyn M
SM
Zinn
Kurt R
KR
Huang
Zhi
Z
Wang
Wenquan
W
Grizzle
William E
WE
Sellers
Jeffrey
J
Stockard
Cecil R
CR
Zhou
Tong
T
Oliver
Patsy G
PG
Arnoletti
Pablo
P
Lobuglio
Albert F
AF
Buchsbaum
Donald J
DJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology*; D011859:Radiography; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D003841:Deoxycytidine; D000093542:Gemcitabine