hTERT-promoter-dependent oncolytic adenovirus enhances the transduction and therapeutic efficacy of replication-defective adenovirus vectors in pancreatic cancer cells.
Adenovirus-mediated gene therapy shows promise for cancer therapy, but transgene expression of replication-defective adenovirus may be low and transient in clinical settings. Recent reports have shown that the use of a conditionally replication-competent adenovirus (CRAd) enhanced the gene transduction of a replication-defective adenovirus vector. The control of tumor-stromal interactions has also been determined to be important in cancer therapy. In this study, we investigated the effect of the human telomerase reverse transcriptase (hTERT)-CRAd, Ad5/3hTERTE1, which possesses the tumor-specific hTERT promoter with the chimeric fiber 5/3, on the transgene expression and therapeutic efficacy of a replication-defective adenovirus vector expressing NK4 under the control of the CMV promoter, Ad-NK4. In addition, we established a new strategy to target both cancer cells and cancer-stromal interactions. Human pancreatic cancer cells were infected with Ad-NK4 and either Ad5/3hTERTE1 (CRAd-combination group) or Ad5/3hTERTLuc (control-combination group). In the CRAd-combination group, Ad-NK4-delivered transgene expression was increased, leading to an enhanced inhibitory effect on the invasion of cancer cells. In in vivo experiments, NK4 expression within tumors and its inhibitory effect on tumor growth, angiogenesis, and metastasis were enhanced in the CRAd-combination group. These results suggest that hTERT-CRAd enhances the transgene expression and therapeutic efficacies of Ad-NK4, possibly through the in-trans replication of Ad-NK4 induced by adenovirus E1 derived from co-infected hTERT-CRAd. This approach may be a promising combination therapy against advanced pancreatic cancer.
Onimaru
Manabu
M
Department of Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ohuchida
Kenoki
K
Mizumoto
Kazuhiro
K
Nagai
Eishi
E
Cui
Lin
L
Toma
Hiroki
H
Takayama
Koichi
K
Matsumoto
Kunio
K
Hashizume
Makoto
M
Tanaka
Masao
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D051379:Mice; D050130:Oncolytic Virotherapy; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*; D014161:Transduction, Genetic
C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C509186:TERT protein, human; D019098:Telomerase