Enhanced Antitumor Efficacy of a DR5-Specific TRAIL Variant over Recombinant Human TRAIL in a Bioluminescent Ovarian Cancer Xenograft Model

Abstract

Purpose: 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. Design: 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. Results: 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). Conclusion: 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.

Natural Immunity Enhances the Activity of a DR5 Agonistic Antibody and Carboplatin in the Treatment of Ovarian Cancer

“…1B and 2C). It has been recently shown that a modified TRAIL ligand that specifically binds to DR5 has a more pronounced apoptotic effect dependent on cisplatin-induced DR5 expression than TRAIL in vitro as well as in an orthotopic bioluminescent ovarian cancer mouse model (41). Collectively, the described data support the importance of drug-induced DR5 upregulation in the enhanced sensitivity of ovarian cancer cells to TRAIL-induced apoptosis.…”

New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants

“…A positive cooperation between cisplatin and TRAIL ligands/agonists has been reported in different preclinical models of colon carcinoma, esophageal squamous cell carcinoma, ovarian cancer, and NSCLC (Duiker et al, 2009;Frese et al, 2009;Kondo et al, 2006;Lacour et al, 2003;Reddy et al, 2004). TRAIL agonists have achieved the clinical setting (Pennarun et al, 2010).…”

Intraoperative Near-Infrared Fluorescence Tumor Imaging with Vascular Endothelial Growth Factor and Human Epidermal Growth Factor Receptor 2 Targeting Antibodies

“…Development of the luciferase-transfected subline A2780 luc1 was described by Duiker et al (17). The SK-BR-3 (HER2-overexpressing) breast cancer and KATO-III (HER2-overexpressing) gastric cancer cell lines were obtained from American Type Culture Collection.…”