A fiber-modified, secretory leukoprotease inhibitor promoter-based conditionally replicating adenovirus for treatment of ovarian cancer.
OBJECTIVE
The use of conditionally replicating adenoviruses (CRAD) is dependent on molecular differences between tumor cells and nontumor cells. Transcriptional targeting of CRAD replication via tumor-specific promoters is an effective way to control replication regulation. Genetic fiber pseudotyping is an approach for circumventing low expression of the primary adenovirus serotype 5 (Ad5) receptor by using the distinct adenovirus serotype 3 (Ad3) receptor for entry into and subsequent killing of ovarian cancer cells.


METHODS
In this study, we constructed a fiber-modified CRAD containing the secretory leukoprotease inhibitor (SLPI) promoter to control viral replication via the E1A gene (Ad5/3SLPI). To evaluate the liver toxicity of chimeric 5/3 fiber-modified CRADs, we compared Ad5/3SLPI with Ad5/3Cox-2L, a CRAD with E1A under control of the Cox-2 promoter, and Ad5/3Delta24, a CRAD that replicates in cancer cells inactive in the retinoblastoma/p16 pathway by use of an in vivo hepatotoxicity model and by a model system that uses slices of human liver.


RESULTS
We show efficient viral replication and oncolysis of Ad5/3SLPI in both multiple ovarian cancer cell lines and primary tumor cell spheroids as well as therapeutic efficacy in an orthotopic mouse model of peritoneal carcinomatosis. Ad5/3SLPI showed significantly decreased liver toxicity compared with other 5/3 fiber-modified control vectors examined.


CONCLUSIONS
In summary, Ad5/3SLPI is a promising vector candidate for treating metastatic ovarian cancer and showed robust virus replication, oncolysis, and in vivo therapeutic efficacy. Ad5/3SLPI showed comparatively low liver toxicity and therefore holds potential for patient use in the clinic.
Rein
Daniel T
DT
Division of Human Gene Therapy, Department of Medicine, Gene Therapy Center, University of Alabama at Birmingham, 901 19th Street South, Birmingham, AL 35294-2172, USA.
Breidenbach
Martina
M
Kirby
Tyler O
TO
Han
Tie
T
Siegal
Gene P
GP
Bauerschmitz
Gerd J
GJ
Wang
Minghui
M
Nettelbeck
Dirk M
DM
Tsuruta
Yuko
Y
Yamamoto
Masato
M
Dall
Peter
P
Hemminki
Akseli
A
Curiel
David T
DT
D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor; D018874:Spheroids, Cellular / Q000473:pathology / Q000821:virology; D016019:Survival Analysis; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D017500:Adenovirus E1A Proteins; D036022:Capsid Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D012333:RNA, Messenger; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; C018315:hexon capsid protein, Adenovirus