Márquez-Gutiérrez Miguel A, Benítez-Hess María L, DiPaolo Joseph A, Alvarez-Salas Luis M
Laboratorio de Terapia Génica, Departamento de Genética y Biología Molecular, CINVESTAV, México DF, México.
Arch Med Res. 2007 Oct;38(7):730-8. doi: 10.1016/j.arcmed.2007.04.011. Epub 2007 Jul 26.
Cervical cancer is highly associated with human papillomavirus (HPV) E6 and E7 gene expression. We have previously reported two antisense oligodeoxynucleotides (AS-ODNs) directed against adjacent targets within the HPV-16 E6/E7 mRNA (419 and 434), each able to downregulate HPV-16 E6/E7 mRNA in vitro and in vivo and to specifically inhibit tumor cell growth in culture and animal models.
Towards potential clinical application and improved in vivo performance, we analyzed the effect of the combined treatment of 419-434 AS-ODNs on the anchorage independent growth (AIG) of HPV-16-positive cervical carcinoma cell lines.
We found similar responses between combined 419-434 and individual AS-ODNs treatments in RNaseH assays, cell uptake, and in vivo degradation of HPV-16 E6/E7 transcripts. Moreover, the combined use of 419-434 AS-ODNs resulted in additive AIG inhibition of CaSki and SiHa cells, similar to that obtained with equivalent doses of the individual AS-ODNs.
By using a combined treatment, it may be possible to overcome the potential mutations frequently reported within HPV-16 genome, thus improving the potential application of 419 and 434 AS-ODNs as a therapeutic alternative for cervical cancer.
宫颈癌与人乳头瘤病毒（HPV）E6和E7基因表达高度相关。我们之前报道过两种反义寡脱氧核苷酸（AS-ODN），它们靶向HPV-16 E6/E7 mRNA内相邻的靶点（419和434），每种都能在体外和体内下调HPV-16 E6/E7 mRNA，并在培养和动物模型中特异性抑制肿瘤细胞生长。
为了实现潜在的临床应用并改善体内性能，我们分析了419 - 434 AS-ODN联合治疗对HPV-16阳性宫颈癌细胞系锚定非依赖性生长（AIG）的影响。
我们发现在核糖核酸酶H分析、细胞摄取以及HPV-16 E6/E7转录本的体内降解方面，419 - 434联合治疗与单独使用AS-ODN治疗的反应相似。此外，419 - 434 AS-ODN联合使用对CaSki和SiHa细胞的AIG抑制具有累加作用，类似于使用等量单独AS-ODN所获得的效果。
通过联合治疗，有可能克服HPV-16基因组中频繁报道的潜在突变，从而提高419和434 AS-ODN作为宫颈癌治疗替代方案的潜在应用价值。
