Conditionally replicating E1B-deleted adenovirus driven by the squamous cell carcinoma antigen 2 promoter for uterine cervical cancer therapy.
Cervical cancer is the second most common type of malignant tumor among women worldwide. When the disease is confined locally, it can be controlled with surgical resection and radiotherapy. However, patients with recurrent or metastatic disease often have a poor prognosis. Measurement of serum levels of squamous cell carcinoma (SCC) antigens has been widely used as serological markers for SCC of uterine cervix. Recently, it has been demonstrated that cervical cancer patients with elevated squamous cell carcinoma antigen-2 (SCCA2) expression in tumor cells carry a poor prognosis. Here, by using a luciferase reporter assay, we show that SCCA2 promoter was active in SCCA2-producing human cervical cancer cell lines, including Cx, Cxwj, SiHa and HeLa cells, but relatively quiescent in normal cervical epithelial cells. We then developed a conditionally replicating adenovirus, designated Ad-KFH, under the transcriptional control of the SCCA2 promoter. This E1B-55 kDa-deleted oncolytic adenovirus replicated specifically in and lysed SCCA2-producing cervical cancer cells. Furthermore, in a peritoneal metastatic tumor model, Ad-KFH retarded Cxwj tumor growth in NOD/severe combined immunodeficient mice and prolonged survival of tumor-bearing mice, especially when combined with cisplatin. These results suggest that Ad-KFH may provide a new strategy of gene therapy for advanced or recurrent uterine cervical cancer.
Hsu
K-F
KF
Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan, Taiwan.
Wu
C-L
CL
Huang
S-C
SC
Hsieh
J-L
JL
Huang
Y-S
YS
Chen
Y-F
YF
Shen
M-R
MR
Chung
W-J
WJ
Chou
C-Y
CY
Shiau
A-L
AL
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014779:Virus Replication
D017501:Adenovirus E1B Proteins; D000951:Antigens, Neoplasm; D017931:DNA Primers; D015843:Serpins; C051072:squamous cell carcinoma-related antigen