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

Evelien W. Duiker, Elisabeth G. E. de Vries, Devalingam Mahalingam, Gert Jan Meersma, Wytske Boersma-van Ek, Harry Hollema, Marjolijn N. Lub-de Hooge, Go M. van Dam, Robbert H. Cool, Wim J. Quax, Afshin Samali, Ate G. J. van der Zee, Steven de Jong*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2048-2057
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number6
DOIs
Publication statusPublished - 15-Mar-2009

Keywords

  • APOPTOSIS-INDUCING LIGAND
  • RECEPTOR-SELECTIVE MUTANTS
  • CARCINOMA CELL-LINES
  • INTRAPERITONEAL CHEMOTHERAPY
  • DEATH RECEPTORS
  • DECOY RECEPTORS
  • TARGETING DEATH
  • BINDING-SITE
  • RESISTANCE
  • EXPRESSION

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