Synergistic antitumor effect of adenovirus armed with Drosophila melanogaster deoxyribonucleoside kinase and nucleoside analogs for human breast carcinoma in vitro and in vivo

Abstract

Miao Tang,1 Cong Zu,2 Anning He,2 Wenqian Wang,1 Bo Chen,1 Xinyu Zheng1,2 1Department of Breast Surgery, The First Hospital of China Medical University, 2Laboratory 1, Cancer Institute, China Medical University, Shenyang, People’s Republic of China Background: Suicide gene therapy in cancer can selectively kill tumors without damaging normal tissues. Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK), an original suicide kinase, makes use of the carcinomatous suicide gene therapy for broader substrate specificity and a higher catalytic rate.Methods: To enhance the anti-tumor efficacy of Dm-dNK and maintain its substrate specificity and safety control in the meantime, the conditionally replicative gene–viral system, ZD55–dNK (which contains the selective replication adenovirus, ZD55, encoded with Dm-dNK), was investigated in pushing a deeper development of this strategy. Selective replication, cell killing efficacy, and cytotoxicity, in combination with chemotherapy, were applied to two breast cell lines (MDA231 and MCF7 cells), two normal cell lines (WI38 and MRC5 cells), and the MCF7 xenograft model in vivo.Results: The preclinical study showed that ZD55–dNK, combined with 2',2'-difluorodeoxycytidine (DFDC), synergistically inhibited adenovirus replication in vitro but maintained specifically cancer cell killing efficacy. ZD55–dNK also greatly improved the antineoplastic effect in vitro and in breast cancer xenograft in vivo.Conclusion: The concomitant use of ZD55–dNK and DFDC is possibly a novel and promising approach to breast cancer treatment, and further investigation on the safe control of excessive virus replication and the efficacy of this approach in humans is warranted. Keywords: Dm-dNK, oncolytic adenovirus, cancer suicide gene therapy, nucleoside analogs, safety control