[Application of antisense oligonucleotides into treatment of human cervical carcinoma].
Antisense oligodeoxynucleotides (oligomers) have critical roles for drugs targeted specifically against oncogenes. We obtained evidence for the inhibitory effects of oligomers to the E6/E7 region of human papilloma virus (HPV) types 16 and 18 on cervical epithelial cells. These cells contained PHK16 cells that was the human keratinocytes immortalized by HPV16 full genome transfection, and C4II cells that was the cervical carcinoma cells harboring HPV 18 genome. The oligomers greatly reduced both cell numbers and H3-thymidine uptake in these cells. This potent antiproliferative activity accompanied the suppression of target gene expression. In contrast, the effects on SiHa cells that contained the HPV16 E6/E7 region were less remarkable. The inhibitory effects did not accompany noticeable inhibition of E7 protein synthesis. Comparison of fluorescent histograms between PHK16 and SiHa cells exposed to a FITC-conjugated oligomer revealed the absence of any significant differences in intra cellular uptake. Thus, the relationship among effects of the oligomers, the subcellular distribution and the binding capability to target genes has to be considered for the inconsistant effects of oligomers. We synthesized the psoralen-conjugated oligomers to enhance the binding capability of oligomers. SiHa cell proliferation could be inhibited by the combination of this psoralen-conjugated oligomers and ultraviolet irradiation even if none of inhibitory effects could be recognized in proliferation of normal human epidermal keratinocytes. Thus, oligomers had potent biological actions of growth inhibition and the eventual death of carcinoma cells. These are critical advantages for drugs specifically against HPV E6/E7 oncogenes.
Wake
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Medical Institute of Bioregulation Kyushu University, Ohita.
D002455:Cell Division / Q000187:drug effects; D003864:Depression, Chemical; D005260:Female; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000473:pathology; D014412:Tumor Virus Infections / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000628:therapy*
D016376:Oligonucleotides, Antisense