Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer.
A phase I dose-escalation study of telomerase-specific oncolytic adenovirus, OBP-301 (Telomelysin), is now under way in the United States to assess feasibility and to characterize its pharmacokinetics in patients with advanced solid tumors. The present preclinical study investigates whether OBP-301 and a chemotherapeutic agent that is commonly used for lung cancer treatment, gemcitabine, are able to enhance antitumor effects in vitro and in vivo. The antitumor effects of OBP-301 infection and gemcitabine were evaluated by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt assay. In vivo antitumor effects of intratumoral injection of OBP-301 in combination with systemic administration of gemcitabine were assessed on nu/nu mice s.c. xenografted with human lung tumors. OBP-301 infection combined with gemcitabine resulted in very potent synergistic cytotoxicity in human lung cancer cells. The three human lung cancer cell lines treated with OBP-301 for 24 hours tended to accumulate in S phase compared with controls. The proportion of cells in S phase increased from 43.85% to 56.41% in H460 cells, from 46.72% to 67.09% in H322 cells, and from 38.22% to 57.67% in H358 cells. Intratumoral injection of OBP-301 combined with systemic administration of gemcitabine showed therapeutic synergism in human lung tumor xenografts. Our data suggest that the combination of OBP-301 and gemcitabine enhances the antitumor effects against human lung cancer. We also found that the synergistic mechanism may be due to OBP-301-mediated cell cycle accumulation in S phase. These results have important implications for the treatment of human lung cancer.
Center for Gene and Cell Therapy, Okayama University Hospital, and Department of Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Dong
D
Liu
Toru
T
Kojima
Masaaki
M
Ouchi
Shinji
S
Kuroda
Yuichi
Y
Watanabe
Yuuri
Y
Hashimoto
Hideki
H
Onimatsu
Yasuo
Y
Urata
Toshiyoshi
T
Fujiwara
D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000473:pathology / Q000628:therapy* / Q000821:virology; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015153:Blotting, Western; D018287:Carcinoma, Large Cell / Q000473:pathology / Q000628:therapy* / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D019098:Telomerase / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D017500:Adenovirus E1A Proteins; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D019098:Telomerase; D000093542:Gemcitabine