Markedly Enhanced Cytolysis by E1B-19kD -Deleted Oncolytic Adenovirus in Combination with Cisplatin

Oncolytic adenoviruses are currently being developed as novel antitumor therapeutics. To enhance their therapeutic potential, adenoviruses are being administered in combination with standard chemotherapy. Adenoviral vectors used in these clinical trials, however, can be destructive as they encode intact E1B 19-kDa protein, which can block the apoptotic pathway induced by a variety of chemotherapeutic agents. Previously, we have shown that oncolytic adenovirus Ad-ΔE1B19/55, deleted for sequence encoding E1B 19-kDa and E1B 55-kDa proteins, exhibits marked enhancement in cytolytic and apoptotic activity [Kim, J., Cho, J.Y., Kim, J.H., Jung, K.C., and Yun, C.O. (2002). Cancer Gene Ther. 9, 725–736]. In the current study, we assess the therapeutic value of Ad-ΔE1B55 and Ad-ΔE1B19/55 in combination with cisplatin. A marked increase in cytotoxicity was observed for both Ad-ΔE1B55 and Ad-ΔE1B19/55 when combined with cisplatin. Relative to each other in all cell lines examined, the combination of the double-deleted adenovirus, Ad-ΔE1B19/55, plus cisplatin exhibited a greater cell-killing effect than did the single-deleted adenovirus, Ad-ΔE1B55, plus cisplatin. Propidium iodide staining and TUNEL analysis also revealed that the combination of cisplatin with Ad-ΔE1B19/55 caused greater induction of apoptosis than that with Ad-ΔE1B55. Similarly, in vivo, the combination of Ad-ΔE1B55 or Ad-ΔE1B19/55 with cisplatin also induced greater antitumor effect in a human cervical xenograft model. TUNEL staining showed that the apoptotic level was significantly higher in tumor tissue treated with Ad-ΔE1B19/55 plus cisplatin than with any other treatment. In addition, viral presence was confirmed by immunohistological staining, with increased numbers of adenoviral particles detected in wider areas of tumors treated with Ad-ΔE1B19/55 oncolytic adenovirus plus cisplatin. Taken together, these findings demonstrate that cisplatin in combination with E1B- 19kD-deleted oncolytic adenovirus may enhance therapeutic efficacy (via active induction of apoptosis), eliciting a greater efficacy profile than that with E1B-19kD-expressing oncolytic adenovirus.