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


METHODS
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).


CONCLUSIONS
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.
Duiker
Evelien W
EW
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
de Vries
Elisabeth G E
EG
Mahalingam
Devalingam
D
Meersma
Gert Jan
GJ
Boersma-van Ek
Wytske
W
Hollema
Harry
H
Lub-de Hooge
Marjolijn N
MN
van Dam
Go M
GM
Cool
Robbert H
RH
Quax
Wim J
WJ
Samali
Afshin
A
van der Zee
Ate G J
AG
de Jong
Steven
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D006801:Humans; D008163:Luminescent Measurements; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D053148:Caspase 3; D002945:Cisplatin