Growth inhibition of cervical tumor cells by antisense oligodeoxynucleotides directed to the human papillomavirus type 16 E6 gene.
Human papillomavirus type 16 (HPV-16) is the HPV type most frequently associated with cervical carcinomas. Based on our previous research with anti-HPV ribozymes, we developed a 16-nucleotide antisense oligodeoxynucleotide (AntiE6) able to direct RNase H activity on full-length HPV-16 E6/E7 mRNA. Although the precise mechanism is not completely understood, addition of 50 microM AntiE6 oligodeoxynucleotide in sterile water caused a significant decrease in the growth rate of CaSki and QGU cervical tumor cell lines. In contrast, addition of a mismatched mutant oligodeoxynucleotide (M7) did not affect cell growth after 72 hours. Treatment with AntiE6 resulted in down-regulation of E6/E7 mRNA and an increase in p53 levels in QGU cells. AntiE6 was also able to (>70%) inhibit significantly growth of transplanted cervical tumors in nude mice after 2 weeks treatment using constant delivery by osmotic pumps. These results indicate that the AntiE6 antisense oligodeoxynucleotides can act as a therapeutic agent against cervical carcinomas.
Alvarez-Salas
L M
LM
Laboratory of Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Arpawong
T E
TE
DiPaolo
J A
JA
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D017931:DNA Primers; D005260:Female; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D016914:Ribonuclease H / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000473:pathology*
D017931:DNA Primers; C068651:E6 protein, Human papillomavirus type 16; D016376:Oligonucleotides, Antisense; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D012097:Repressor Proteins; D016914:Ribonuclease H