IN-VITRO AND IN-VIVO INHIBITION OF HUMAN PAPILLOMAVIRUS TYPE-16 E6 AND E7 GENES

Human cervical cancers are often associated with human papillomavirus (HPV). In HPV-positive cervical cancers, the oncoproteins E6 and E7 ar e consistently expressed. In this study, the effects of antisense inhi bition of both proteins were examined. Phosphorothioate oligonucleotid es (ODNs) AE6 and AE7 complementary to regions flanking the start codo ns of HPV16 E6 and E7 genes, respectively, were synthesized. These ant i-HPV ODNs inhibited the growth of cervical cell lines CaSki and SiHa, which harbor HPV16 but had little effect on cells that do not. Both O DNs also affected the ability of CaSki cells to form colonies in soft agar, In nude mice, treatment with either AE6, AE7, or a mixture of bo th led to substantially smaller tumors. AE7 was observed to inhibit E7 synthesis, The AE6 ODN probably exerts its effect by suppressing the expression of E6 as well as E7. Cell cultures and tumors treated with AE6 showed a decrease in E7 expression. In addition, an antisense ODN targeted at the retinoblastoma gene was able to reverse some of the in hibitory effect of AE6 on CaSki cells, indicating that AE6 inhibited E 7 synthesis. This study further demonstrates that anti-HPV ODNs may be useful therapeutically.