+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Enhanced antitumor efficacy of a DR5-specific TRAIL variant over recombinant human TRAIL in a bioluminescent ovarian cancer xenograft model

Enhanced antitumor efficacy of a DR5-specific TRAIL variant over recombinant human TRAIL in a bioluminescent ovarian cancer xenograft model

Clinical Cancer Research 15(6): 2048-2057

Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) is clinically evaluated as novel anticancer drug. rhTRAIL-DR5, a rhTRAIL variant that specifically binds to DR5 receptor, has recently been developed. We investigated whether rhTRAIL-DR5 is more efficient than rhTRAIL in combination with cisplatin in DR5-expressing human A2780 ovarian cancer cells. Effect of cisplatin alone or in combination with rhTRAIL or rhTRAIL-DR5 on DR5 surface expression, apoptosis, and cell survival of A2780 was measured. Biodistribution analysis was done in mice with (125)I-rhTRAIL administered intravenously versus intraperitoneally. Antitumor efficacy of rhTRAIL-DR5 versus rhTRAIL was determined in an intraperitoneally growing bioluminescent A2780 xenograft model. Cisplatin strongly enhanced DR5 surface expression. Both rhTRAIL and rhTRAIL-DR5 in combination with cisplatin induced high levels of caspase-3 activation, apoptosis, and cell kill, with rhTRAIL-DR5 being most potent. Intraperitoneal administration of (125)I-rhTRAIL resulted in a 1.7-fold higher area under the curve in serum, increased tumor exposure, and more caspase-3 activation in the tumor than intravenous administration. Intraperitoneal administration of rhTRAIL-DR5 delayed A2780 tumor progression, reflected in a mean light reduction of 68.3% (P = 0.015), whereas rhTRAIL or rhTRAIL-DR5 plus cisplatin resulted in 85% (P = 0.003) and 97% (P = 0.002) reduction compared with A2780 tumor progression in vehicle-treated animals. Combination of rhTRAIL-DR5 with cisplatin was more effective than cisplatin alone (P = 0.027). rhTRAIL-DR5 was superior over rhTRAIL in vitro and in vivo against DR5-expressing ovarian cancer also in combination with cisplatin. Intraperitoneal administration of rhTRAIL-DR5 warrants further exploration in ovarian cancer.

(PDF emailed within 0-6 h: $19.90)

Accession: 052982143

Download citation: RISBibTeXText

PMID: 19276284

DOI: 10.1158/1078-0432.CCR-08-1535

Related references

Effects of Recombinant Circularly Permuted Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) (Recombinant Mutant Human TRAIL) in Combination with 5-Fluorouracil in Human Colorectal Cancer Cell Lines HCT116 and SW480. Medical Science Monitor 24: 2550-2561, 2018

Enhanced antitumor effect of combining interferon beta with TRAIL mediated by tumor-targeting adeno-associated virus vector on A549 lung cancer xenograft. Sheng Wu Gong Cheng Xue Bao 26(6): 780-788, 2011

Population pharmacokinetic (PPK) analysis of recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) in a Phase 1a Study in advanced cancer and lymphoma. Journal of Clinical Oncology 26(15_suppl): 2525-2525, 2016

TRAIL mutant membrane penetrating peptide alike (TMPPA) TRAIL‑Mu3 enhances the antitumor effects of TRAIL in vitro and in vivo. Molecular Medicine Reports 16(6): 9607-9612, 2017

A human scFv antibody against TRAIL receptor 2 induces autophagic cell death in both TRAIL-sensitive and TRAIL-resistant cancer cells. Cancer Research 67(15): 7327-7334, 2007

Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model. Bmc Urology 13: 1, 2013

The regulation of combined treatment-induced cell death with recombinant TRAIL and bortezomib through TRAIL signaling in TRAIL-resistant cells. Bmc Cancer 18(1): 432, 2018

A novel TRAIL mutant-TRAIL-Mu3 enhances the antitumor effects by the increased affinity and the up-expression of DR5 in pancreatic cancer. Cancer ChemoTherapy and Pharmacology 82(5): 829-838, 2018

Expression of trail receptors and antitumor effects of trail in human hepatocellular carcinoma. Journal of Hepatology 38(Supplement 2): 97, 2003

AD-O53.2--a novel recombinant fusion protein combining the activities of TRAIL/Apo2L and Smac/Diablo, overcomes resistance of human cancer cells to TRAIL/Apo2L. Investigational New Drugs 32(6): 1155-1166, 2015

TRAIL receptor expression and TRAIL responses in ovarian cancer. Proceedings of the American Association for Cancer Research Annual Meeting 42: 313, 2001

The expression of TRAIL, TRAIL-R (DR4, DcR1) and Fas-L in patients with ovarian cancer. Sichuan Da Xue Xue Bao. Yi Xue Ban 36(3): 341-343, 2005

Apoptosis inducing activity of recombinant soluble human Apo2L/TRAIL is enhanced by CPT-11 in human prostate cancer cells. Proceedings of the American Association for Cancer Research Annual Meeting 42: 438, 2001

TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells. Nanotechnology 27(18): 185101, 2016

High susceptibility of metastatic cells derived from human prostate and colon cancer cells to TRAIL and sensitization of TRAIL-insensitive primary cells to TRAIL by 4,5-dimethoxy-2-nitrobenzaldehyde. Molecular Cancer 10: 46, 2011