Ueno N T, Bartholomeusz C, Herrmann J L, Estrov Z, Shao R, Andreeff M, Price J, Paul R W, Anklesaria P, Yu D, Hung M C
Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Clin Cancer Res. 2000 Jan;6(1):250-9.
HER-2/neu-overexpressing breast cancer cells are more resistant to the chemotherapeutic agent paclitaxel (Taxol) than low-HER-2/neu-expressing breast cancer cells, and the adenoviral type 5 EIA can down-regulate HER-2/neu overexpression. Therefore, in this study, we asked (a) whether EIA might sensitize response to paclitaxel in human HER-2/neu-overexpressing ovarian cancer cells, and, if so, what is the mechanism responsible; and (b) whether this enhanced chemosensitivity would translate into a therapeutic effect in an ovarian cancer xenograft model. Consequently, we demonstrated that: (a) adenovirus type 5 E1A could enhance the sensitivity of paclitaxel in paclitaxel-resistant HER-2/neu-overexpressing human ovarian cancer cells in vitro by inducing apoptosis, (b) this induction was heavily dependent on activation of the caspase-3 pathway, and (c) nude mice bearing i.p. HER-2/neu-overexpressing human ovarian cancer cells and treated with both paclitaxel and E1A gene therapy survived significantly longer than did mice treated only with paclitaxel or E1A gene therapy. Thus, we concluded that the E1A gene enhanced both the in vitro and in vivo sensitivity of paclitaxel in paclitaxel-resistant HER-2/ neu-overexpressing ovarian cancer SKOV3.ipl cells. Because a Phase I clinical trial using E1A gene targeted to HER-2/neu down-regulation has recently been completed, the current study also provided a scientific basis to further develop a novel therapy that combines paclitaxel and E1A gene therapy and its testing in a Phase II trial.
与低HER-2/neu表达的乳腺癌细胞相比，HER-2/neu过表达的乳腺癌细胞对化疗药物紫杉醇（泰素）更具抗性，而5型腺病毒EIA可下调HER-2/neu的过表达。因此，在本研究中，我们探讨了：（a）EIA是否能使HER-2/neu过表达的人卵巢癌细胞对紫杉醇敏感，若能，其作用机制是什么；（b）这种增强的化疗敏感性是否能在卵巢癌异种移植模型中转化为治疗效果。结果表明：（a）5型腺病毒E1A可通过诱导凋亡增强耐紫杉醇的HER-2/neu过表达的人卵巢癌细胞对紫杉醇的敏感性；（b）这种诱导严重依赖于半胱天冬酶-3途径的激活；（c）腹腔接种HER-2/neu过表达的人卵巢癌细胞并接受紫杉醇和E1A基因治疗的裸鼠比仅接受紫杉醇或E1A基因治疗的小鼠存活时间显著延长。因此，我们得出结论，E1A基因增强了耐紫杉醇的HER-2/neu过表达的卵巢癌SKOV3.ipl细胞对紫杉醇的体内外敏感性。由于最近已完成一项针对HER-2/neu下调的E1A基因的I期临床试验，本研究也为进一步开发一种将紫杉醇和E1A基因治疗相结合并在II期试验中进行测试的新疗法提供了科学依据。
