TY - JOUR
T1 - E1A-mediated paclitaxel sensitization in HER-2/neu-overexpressing ovarian cancer SKOV3.ip1 through apoptosis involving the caspase-3 pathway
AU - Ueno, Naoto T.
AU - Bartholomeusz, Chandra
AU - Herrmann, John L.
AU - Estrov, Zeev
AU - Shao, Ruping
AU - Andreeff, Michael
AU - Price, Janet
AU - Paul, Ralph W.
AU - Anklesaria, Pervin
AU - Yu, Dihua
AU - Hung, Mien Chie
PY - 2000/1
Y1 - 2000/1
N2 - 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 E1A can down-regulate HER- 2/neu overexpression. Therefore, in this study, we asked (a) whether E1A 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.ip1 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.
AB - 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 E1A can down-regulate HER- 2/neu overexpression. Therefore, in this study, we asked (a) whether E1A 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.ip1 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.
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M3 - Article
C2 - 10656456
AN - SCOPUS:0033978815
SN - 1078-0432
VL - 6
SP - 250
EP - 259
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -