Tumor-specific gene therapy for uterine cervical cancer using MN/CA9-directed replication-competent adenovirus.
Although gene therapies using tissue-specific promoters have been reported to be a promising tool for treating cancers, few studies have explored this possibility for uterine cervical cancer. MN/CA9 is a transmembrane glycoprotein that was first identified in the human cervical carcinoma cell line, HeLa. Since MN/CA9 protein is highly expressed in uterine cervical cancer tissues, but not in normal cervix, we constructed a tumor-specific replication-competent adenoviral vector utilizing MN/CA9 promoter (Ad-MN/CA9-E1a), which can replicate only in MN/CA9-expressing cells. Infection of Ad-MN/CA9-E1a to MN/CA9-positive uterine cervical cancer cells (HeLa, C-33 A and SiHa) resulted in much stronger Ad5 E1a protein expressions compared with MN/CA9-negative cells (SK-RC-29), suggesting a tissue-specific replication of this recombinant adenovirus. In vitro cytotoxicity assay revealed that the growth of MN/CA9-positive cells was significantly inhibited with 0.01-1 MOI of Ad-MN/CA9-E1a, but the growth of MN/CA9-negative cells (SK-RC-29) could only be inhibited by as many as 100 MOI. Intratumoral injection of Ad-MN/CA9-E1a effectively induced growth delay of HeLa tumors in nude mice. These results suggest that a novel replication-competent adenoviral vector mediated by MN/CA9 promoter, Ad-MN/CA9-E1a, can selectively replicate in MN/CA9-expressing tumors with cytotoxic effects and may be utilized for the treatment of uterine cervical cancer.
Lim
Ho Yeong
HY
Department of Medical Oncology, Ajou University School of Medicine, Suwon, Korea.
Ahn
Miwon
M
Chung
Hyun Cheol
HC
Gardner
Thomas A
TA
Kao
Chinghai
C
Lee
Sang-Jin
SJ
Kim
Se Joong
SJ
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D000951:Antigens, Neoplasm; D012333:RNA, Messenger; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases