S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
Combination gene therapy of lung cancer with conditionally replicating adenovirus and adenovirus-herpes simplex virus thymidine kinase
- Oh, Jin Young; Park, Mi Young; Kim, Dal Rae; Lee, Jung Hee; Chung, Jin-Haeng; Lee, Jae Ho; Kim, Yeon-Soo; Lee, Choon-Taek; Sung, Myung-Whun; Yoon, Ho-Il; Shim, Seon-Hui
- Issue Date
- SPANDIDOS PUBL LTD
- INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE; Vol.25 3; 369-376
- conditionally replicating adenovirus; adenovirus-HSTK; lung cancer; combination gene therapy
- A major obstacle to the success of gene therapy strategies that directly target cancer cells is the low gene transfer rate. To address this problem, we had previously proposed a combination adenoviral gene therapy containing a conditionally replicating adenovirus (CRAD) expressing mutant E1 (Delta 24RGD), and a replication-defective E1-deleted adenovirus to enhance the efficiency of gene transfer. Suicide/pro-drug gene therapy has an important additional benefit to the therapy of cancer. This relates to the transfer and expression of non-mammalian genes encoding enzymes that convert non-toxic pro-drugs into cellular toxins. We investigated the interaction between CRAD (Delta 24RGD) and a replication-defective E1-deleted adenovirus (ad-HSTK) containing a suicide gene (HSTK: herpes simplex virus thymidine kinase gene) with respect to therapeutic gene production and tumor cell killing efficacy. Combined transduction of CRAD and ad-HSTK increased the transduction efficiency of HSTK and increased its sensitivity to ganciclovir (GCV) more efficiently than ad-HSTK alone. Transfer of medium of CRAD and ad-HSTK co-transduced cells induced the transfer of HSTK (media transferable bystander effect), and enhanced its sensitivity to GCV. In an animal tumor model, combined intratumoral injection of CRAD and ad-HSTK followed by GCV administration induced prolonged expression of HSTK and stronger growth suppression of established lung cancer xenografts than single injections. These data demonstrate that the selective replication of ad-HSTK due to the presence of mutant E1, produced by a Delta 24RGD and HSTK/GCV suicide gene system, resulted in a striking improvement in anti-tumor effects in vitro and in vivo.