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

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

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  • Medientyp: E-Artikel
  • Titel: Enhanced Antitumor Efficacy of a DR5-Specific TRAIL Variant over Recombinant Human TRAIL in a Bioluminescent Ovarian Cancer Xenograft Model
  • Beteiligte: Duiker, Evelien W.; de Vries, Elisabeth G.E.; Mahalingam, Devalingam; Meersma, Gert Jan; Boersma-van Ek, Wytske; Hollema, Harry; Lub-de Hooge, Marjolijn N.; van Dam, Go M.; Cool, Robbert H.; Quax, Wim J.; Samali, Afshin; van der Zee, Ate G.J.; de Jong, Steven
  • Erschienen: American Association for Cancer Research (AACR), 2009
  • Erschienen in: Clinical Cancer Research, 15 (2009) 6, Seite 2048-2057
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-08-1535
  • ISSN: 1078-0432; 1557-3265
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: 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 125I-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 125I-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.
  • Zugangsstatus: Freier Zugang