Combination of a MDR1-targeted replicative adenovirus and chemotherapy for the therapy of pretreated ovarian cancer.
OBJECTIVE
Targeted oncolytic adenoviruses capable of replication selectively in cancer cells are an appealing approach for the treatment of various cancer types refractory to conventional therapies. The aim of this study was to evaluate the effect of Ad5/3MDR1E1, a multidrug resistance gene 1 (MDR1)-targeted fiber-modified replication-competent adenovirus for the therapy of platinum-pretreated ovarian cancer in combination with cytostatic agents.


METHODS
MDR1-specific tumor cell killing of Ad5/3MDR1E1 was systematically evaluated in chemotherapy naïve and pretreated ovarian cancer cells in vitro. Combinations of Ad5/3MDR1E1 and cytostatic agents were studied in vivo and in vitro. An in vivo hepatotoxicity model was used to evaluate liver toxicity.


RESULTS
We demonstrate efficient oncolysis of Ad5/3MDR1E1 in chemotherapy-resistant ovarian cancer cells as well as therapeutic efficacy in an orthotopic mouse model. Further, combining Ad5/3MDR1E1 with paclitaxel resulted in greater therapeutic benefit than either agent alone.


CONCLUSIONS
These preclinical data suggest that a fiber-modified adenovirus vector under the control of the MDR1 promoter represents a promising treatment strategy for platinum-pretreated ovarian cancer as a single agent or in combination with conventional anticancer drugs.
Department of Obstetrics and Gynecology, University of Düsseldorf Medical Center, Moorenstrasse 5, 40225 Düsseldorf, Germany. daniel.rein@hohenlind.de
Daniel T
DT
Rein
Anne
A
Volkmer
Gerd
G
Bauerschmitz
Ines M
IM
Beyer
Wolfgang
W
Janni
Markus C
MC
Fleisch
Anne Kathrin
AK
Welter
Dirk
D
Bauerschlag
Thomas
T
Schöndorf
Martina
M
Breidenbach
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D036022:Capsid Proteins / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D017239:Paclitaxel / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D036022:Capsid Proteins; C018315:hexon capsid protein, Adenovirus; D017239:Paclitaxel; D002945:Cisplatin