Restoration of Wild-Type p53 by Adenovirus-Mediated Gene Transfer May Enhance the Therapeutic Efficacy of Chemotherapy in Human Ovarian Cancer Cells

Kim, Tae Eung; Kim, Yong Wook; Kim, Heung Ki; Ro, Duck Yeong; Kim, Jin Woo; Jung, Jae Keun; Kieback, Dirk G; Namkoong, Sung Eun

Abstract

OBJECTIVE
In an effort to develop a more effective therapeutic strategy for ovarian cancer, we examined whether the restoration of the wild-type p53 gene can enhance the therapeutic effect of chemotherapy.
METHODS
In this study, Ov-ca-2774 cells, which are known to have p53 point mutation and cisplatin-resistance, were selected and currently used chemotherapeutic agents including cisplatin, carboplatin, paclitaxel, etoposide, topotecan, and doxorubicin were added concurrently or sequentially with adenovirus-mediated p53 gene transfer (Ad5CMV-p53).
RESULTS
Transfer of the wild-type p53 cDNA gene into Ov-ca-2774 cells showed 55% cell killing in vitro at a multiplicity of infection (MOI) of 40. Although the combination of carboplatin or paclitaxel followed by p53 gene transfer with an interval of 48 h manifested no enhanced cell killing compared with cells infected with Ad5CMV-p53 alone, the other combinations of chemotherapeutic agents and p53 gene transfer resulted in 15% to 37% further cell killing (P<0.05). Furthermore, p53 gene transfer followed by doxorubicin with an interval of 24 h and concurrent combination of etoposide with p53 gene transfer showed significant difference in cell killing in contrast to the other combination strategies in the respective chemotherapeutic agent exposure groups (P<0.05).
CONCLUSION
Our data demonstrated that combination of p53 gene transfer and chemotherapeutic agents had higher cell killing than either of these two modality alone.