Egami Takuya, Ohuchida Kenoki, Miyoshi Kei, Mizumoto Kazuhiro, Onimaru Manabu, Toma Hiroki, Sato Norihiro, Matsumoto Kunio, Tanaka Masao
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Cancer Sci. 2009 Apr;100(4):722-9. doi: 10.1111/j.1349-7006.2009.01101.x. Epub 2009 Mar 11.
Adenovirus-mediated gene therapy combined with chemotherapeutic agents is expected to represent a new approach for treating pancreatic cancer. However, there have been no reports of definitive effects of chemotherapeutic agents on adenovirus-mediated gene therapies. In the present study, we investigated the effects of chemotherapeutic agents on the transduction efficiency of an adenovirus-based gene therapy. Adenovirus (Ad-NK4) expressing NK4, which acts as a hepatocyte growth factor antagonist, was used as a representative gene therapy. Pancreatic cancer cells infected with Ad-NK4 were treated with chemotherapeutic agents (5-fluorouracil [5FU], cisplatin or etoposide), and the NK4 levels in their culture media were measured. To examine the effects of chemotherapeutic agents in vivo, Ad-NK4 was administered to subcutaneous tumors in mice after treatment with the agents, and the tumor NK4 levels were measured. The NK4 levels in culture media from cells treated with 5FU, cisplatin and etoposide were 5.2-fold (P = 0.026), 6-fold (P < 0.001) and 4.3-fold (P < 0.001) higher than those of untreated cells, respectively. The chemotherapeutic agents also increased Ad-NK4 uptake. The NK4 levels in tumors treated with 5FU, cisplatin and etoposide were 5.4-fold (P = 0.006), 11.8-fold (P < 0.001) and 4.9-fold (P = 0.017) higher than those in untreated tumors, respectively. The present findings suggest that chemotherapeutic agents significantly improve the efficiency of adenovirus-mediated gene transfer in pancreatic cancer. Furthermore, they will contribute to decreases in the adenovirus doses required for gene transfer, thereby controlling the side-effects of adenovirus infection in normal tissues.
腺病毒介导的基因治疗联合化疗药物有望成为治疗胰腺癌的一种新方法。然而，尚无关于化疗药物对腺病毒介导的基因治疗的确切效果的报道。在本研究中，我们调查了化疗药物对基于腺病毒的基因治疗转导效率的影响。表达作为肝细胞生长因子拮抗剂的NK4的腺病毒（Ad-NK4）被用作代表性的基因治疗。用化疗药物（5-氟尿嘧啶[5FU]、顺铂或依托泊苷）处理感染Ad-NK4的胰腺癌细胞，并测量其培养基中的NK4水平。为了研究化疗药物在体内的作用，在用这些药物处理后将Ad-NK4注射到小鼠的皮下肿瘤中，并测量肿瘤中的NK4水平。用5FU、顺铂和依托泊苷处理的细胞的培养基中的NK4水平分别比未处理细胞高5.2倍（P = 0.026）、6倍（P < 0.001）和4.3倍（P < 0.001）。化疗药物还增加了Ad-NK4的摄取。用5FU、顺铂和依托泊苷处理的肿瘤中的NK4水平分别比未处理肿瘤高5.4倍（P = 0.006）、11.8倍（P < 0.001）和4.9倍（P = 0.017）。目前的研究结果表明，化疗药物可显著提高腺病毒介导的基因转移在胰腺癌中的效率。此外，它们将有助于减少基因转移所需的腺病毒剂量，从而控制腺病毒感染在正常组织中的副作用。
