Treatment of pancreatic cancer with anti-death receptor antibody in combination with Gemcitabine

DeRosier, Leo Christopher; Buchsbaum, Donald J.; Sellers, Jeffrey C.; Huang, Zhiqiang; Oliver, Patsy G.; Vickers, Selwyn M.

doi:10.1016/j.jamcollsurg.2005.06.018

Cited by 1 publication

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“…However, the orthotopic model is a more accurate physiologic model for parenchymal and metastatic tumor invasion as well as pharmacokinetic drug delivery (62 -66). Our previous work showed a significant improvement with combination TRA-8 and gemcitabine treatment of s.c. MIA PaCa2 xenografts versus monotherapy for single-cycle treatment (35,67). However, to more closely resemble the clinical efficacy and toxicity of multiple cycles of CPT-11 (35,67), two 10-day cycles of combination treatment were used in this study.…”

Section: Discussionmentioning

confidence: 99%

“…However, it has been humanized and is being investigated in an ongoing clinical trial. Second, whereas the TRA-8 -resistant cell line S2VP10 showed increased sensitivity to TRA-8 when pretreated with CPT-11, in vivo studies (data not shown) have not produced a substantial survival benefit with this cell line (35,67). Third, complete profiling of these cell lines was not done with DNA microarray or two-dimensional gels to determine whether multiple other resistance mechanisms were present.…”

Section: Discussionmentioning

confidence: 99%

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Combination Treatment with TRA-8 Anti–Death Receptor 5 Antibody and CPT-11 Induces Tumor Regression in an Orthotopic Model of Pancreatic Cancer

DeRosier¹,

Buchsbaum

Oliver

et al. 2007

Clinical Cancer Research

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Purpose: Evaluate the response of human pancreatic cancer cell lines and orthotopic tumors to TRA-8, an agonistic antibody to death receptor 5, in combination with irinotecan (CPT-11). Experimental Design: MIA PaCa-2 and S2VP10 cells were treated withTRA-8 and/or CPT 11. Cell viability was determined by ATP assay. JC-1 mitochondrial depolarization and Annexin V assays confirmed cell death by apoptosis. Immunoblotting was used to evaluate protein changes. MIA PaCa-2 cells were injected into the pancreas of severe combined immunodeficient mice. Mice underwent abdominal ultrasound to quantitate tumor size before and after treatment with twice weekly injections of 200 Ag TRA-8 and/or 25 mg/kg CPT-11 for one or two treatment cycles, each lasting 2 weeks. Results: MIA PaCa-2 cells were more sensitive to TRA-8 and showed additive cytotoxicity, whereas S2VP10 cells showed synergistic cytotoxicity when treated with TRA-8 and CPT-11. Cell death occurred via apoptosis with increased cleavage of caspase-3, caspase-8, and caspase-9 and proapoptotic proteins Bid and poly(ADP)ribose polymerase after combination treatment compared with either agent alone. XIAP and Bcl-XL inhibitors of apoptosis were down-regulated. After a single cycle of in vivo combination therapy, tumor sizes had diminished significantly (P < 0.001) at 8 days posttreatment compared with no treatment, CPT-11, and TRA-8; and there was a 50-day increase in survival with combination treatment over untreated controls (P = 0.0002), 30 days over TRA-8, and a 36-day increase over CPT-11 monotherapy (P = 0.0003). With two cycles of TRA-8/CPT-11 treatment, mean survival time increased significantly (P < 0.001) to 169 days versus untreated controls, TRA-8 or 121, or 108 days, respectively). Conclusions: Combination TRA-8 and CPT-11 therapy produced enhanced cytotoxicity and survival in the MIA PaCa-2 orthotopic model of pancreatic cancer.

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