Gene transfer to cervical cancer with fiber-modified adenoviruses.
Successful adenoviral (Ad) vector-mediated strategies for cancer gene therapy mandate gene-delivery systems that are capable of achieving efficient gene delivery in vivo. In many cancer types, in vivo gene-transfer efficiency remains limited due to the low or highly variable expression of the primary Ad receptor, the coxsackie Ad receptor (CAR). In this study, we evaluated the expression of CAR on cervical cancer cells as well as CAR-independent targeting strategies to integrins (Ad5.RGD), heparan sulfate proteoglycans (Ad5.pK7) or both (Ad5.RGD.pK7). We used a panel of established cervical cancer cell lines and primary cervical cancer cells isolated from patients to quantify the expression of CAR mRNA and to evaluate the gene-transfer efficiency of fiber-modified Ads. Of the fiber-modified vectors, Ad5.pK7 and Ad5.RGD.pK7 displayed significantly enhanced gene-transfer efficiency in vitro. Gene-delivery efficiency in vivo was evaluated using an s.c. cervical cancer mouse model. Ad5.RGD.pK7 significantly improves tumor targeting in vivo, resulting in a significantly improved tumor/liver ratio in mice. Our results suggest that the double-modified Ad5.RGD.pk7 vector enhances gene transfer to clinically relevant cervical cancer substrates, while the infectivity of nontarget cells in the mouse is not increased and comparable to Ad5. The fiber-modified virus described here can help achieve higher clinical efficacy of cervical cancer gene therapy.
Rein
Daniel T
DT
Division of Human Gene Therapy, Departments of Medicine, Surgery and Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA.
Breidenbach
Martina
M
Wu
Hongju
H
Han
Tie
T
Haviv
Yosef S
YS
Wang
Minghui
M
Kirby
Tyler O
TO
Kawakami
Yosuke
Y
Dall
Peter
P
Alvarez
Ronald D
RD
Curiel
David T
DT
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004770:Enterovirus / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D016023:Integrins; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D011991:Receptors, Virus / Q000096:biosynthesis* / Q000235:genetics*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000628:therapy*
D016023:Integrins; D012333:RNA, Messenger; D011991:Receptors, Virus; C085301:adenovirus receptor