TY - JOUR
T1 - Oncolytic adenovirus expressing a p53 variant resistant to degradation by HPV E6 protein exhibits potent and selective replication in cervical cancer
AU - Heideman, Daniëlle A.M.
AU - Steenbergen, Renske D.M.
AU - van der Torre, Jaco
AU - Scheffner, Martin
AU - Alemany, Ramon
AU - Gerritsen, Winald R.
AU - Meijer, Chris J.L.M.
AU - Snijders, Peter J.F.
AU - van Beusechem, Victor W.
N1 - Funding Information:
We thank Sander Spiekstra, Melanie Breetveld, and Sue Gibbs (Department of Dermatology, VU University Medical Center) for their help in obtaining primary keratinocytes. We thank Jeroen Mastenbroek (Division of Gene Therapy, Department of Medical Oncology, VU University Medical Center) and Wil Dekker (Department of Pathology, VU University Medical Center) for expert technical assistance. We thank Erik Hooijberg (Department of Pathology, VU University Medical Center) and Ruud Brakenhoff (Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center) for helpful discussions. R.D.M.S. and V.W.v.B. are supported by research fellowships of the Royal Netherlands Academy of Arts and Sciences.
PY - 2005/12
Y1 - 2005/12
N2 - Rationale in the development of novel treatment strategies for HPV-associated cancers is targeting on the basis of the presence of HPV in (pre)malignant cells. Here, we designed a new conditionally replicating adenovirus (CRAd) for selective and effective oncolytic replication in HPV-containing cells. As the backbone, we used the CRAd AdCB016, which replicates selectively in cells expressing HPV E6 and E7 proteins. To enhance its oncolytic potency, we armed AdCB016 with p53 variant mp53(268N), which is resistant to HPV E6-mediated degradation. The new CRAd AdCB016-mp53(268N) was analyzed for its lytic replication properties in cervical carcinoma cell lines, HPV-immortalized keratinocyte cell lines representing dysplastic cells, and primary human keratinocytes. AdCB016-mp53(268N) exhibited 10- to 1000-fold greater efficacy than AdCB016 on high-risk HPV-positive cervical carcinoma cells and HPV-immortalized keratinocytes. Importantly, infection with AdCB016-mp53(268N) did not affect primary nonmalignant human keratinocytes. This favorable efficacy and safety profile was confirmed in organotypic raft cultures. Our findings suggest that AdCB016-mp53(268N) is a promising new agent for treatment of HPV-associated human cancers.
AB - Rationale in the development of novel treatment strategies for HPV-associated cancers is targeting on the basis of the presence of HPV in (pre)malignant cells. Here, we designed a new conditionally replicating adenovirus (CRAd) for selective and effective oncolytic replication in HPV-containing cells. As the backbone, we used the CRAd AdCB016, which replicates selectively in cells expressing HPV E6 and E7 proteins. To enhance its oncolytic potency, we armed AdCB016 with p53 variant mp53(268N), which is resistant to HPV E6-mediated degradation. The new CRAd AdCB016-mp53(268N) was analyzed for its lytic replication properties in cervical carcinoma cell lines, HPV-immortalized keratinocyte cell lines representing dysplastic cells, and primary human keratinocytes. AdCB016-mp53(268N) exhibited 10- to 1000-fold greater efficacy than AdCB016 on high-risk HPV-positive cervical carcinoma cells and HPV-immortalized keratinocytes. Importantly, infection with AdCB016-mp53(268N) did not affect primary nonmalignant human keratinocytes. This favorable efficacy and safety profile was confirmed in organotypic raft cultures. Our findings suggest that AdCB016-mp53(268N) is a promising new agent for treatment of HPV-associated human cancers.
KW - AdCB016
KW - AdΔ24
KW - CIN
KW - CRAd
KW - Cervical cancer
KW - HPV
KW - Organotypic raft culture
KW - Primary keratinocyte
KW - Virotherapy
KW - p53
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U2 - 10.1016/j.ymthe.2005.06.443
DO - 10.1016/j.ymthe.2005.06.443
M3 - Article
C2 - 16085463
AN - SCOPUS:28444495859
VL - 12
SP - 1083
EP - 1090
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 6
ER -