Targeting oncogenes to improve breast cancer chemotherapy
Targeting oncogenes to improve breast cancer chemotherapy
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DOI：
10.1158/0008-5472.can-05-4288
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发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Vasquez, KM
中科院分区：
文献类型：
--
作者：
Christensen, LA;Finch, RA;Vasquez, KM
尽管最近在治疗方面取得了进展，但乳腺癌仍然对女性健康构成严重威胁。传统化疗由于缺乏对肿瘤细胞的特异性以及许多化疗药物的细胞周期依赖性而受到限制。在这里，我们报告了一种新的策略来帮助克服这些限制。使用三链体形成寡核苷酸（TFO）将 DNA 损伤位点特异性地定向到人类乳腺癌细胞中过度表达的癌基因，我们证明抗癌核苷类似物吉西他滨的有效性可以显着提高。靶向 c-myc 启动子区域的 TFO 直接抑制基因表达约 40%。当联合使用时，特定的 TFO 使吉西他滨在靶位点的掺入量增加了大约 4 倍，这可能是由于诱导了不依赖于复制的 DNA 合成。用 TFO 和吉西他滨联合处理的细胞显示出细胞存活率和不依赖于贴壁的生长能力的降低（与未处理细胞的 19% 相似）。与单独治疗相比，这种组合对这些癌细胞的致瘤潜力的影响程度显着更大。这种新策略可用于增加抗肿瘤核苷在任何过度表达可靶向癌基因的肿瘤中的有效性范围。诸如此类的多方面化疗方法，加上三重定向基因靶向，可能会带来乳腺肿瘤非手术治疗的渐进式改善。
Despite recent advances in treatment, breast cancer remains a serious health threat for women. Traditional chemotherapies are limited by a lack of specificity for tumor cells and the cell cycle dependence of many chemotherapeutic agents. Here we report a novel strategy to help overcome these limitations. Using triplex-forming oligonucleotides (TFOs) to direct DNA damage site-specifically to oncogenes overexpressed in human breast cancer cells, we show that the effectiveness of the anticancer nucleoside analogue gemcitabine can be improved significantly. TFOs targeted to the promoter region of c-myc directly inhibited gene expression by similar to 40%. When used in combination, specific TFOs increased the incorporation of gemcitabine at the targeted site similar to 4-fold, presumably due to induction of replication-independent DNA synthesis. Cells treated with TFOs and gemcitabine in combination showed a reduction in both cell survival and capacity for anchorage-independent growth (similar to 19% of untreated cells). This combination affected the tumorigenic potential of these cancer cells to a significantly greater extent than either treatment alone. This novel strategy may be used to increase the range of effectiveness of antitumor nucleosides in any tumor which overexpresses a targetable oncogene. Multifaceted chemotherapeutic approaches such as this, coupled with triplex-directed gene targeting, may lead to more than incremental improvements in nonsurgical treatment of breast tumors.