Chemotherapeutic agents potentiate adenoviral gene therapy for pancreatic cancer
Chemotherapeutic agents potentiate adenoviral gene therapy for pancreatic cancer
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DOI：
10.1111/j.1349-7006.2009.01101.x
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发表时间：
2009-04-01
期刊：
影响因子：
5.7
通讯作者：
Tanaka, Masao
中科院分区：
文献类型：
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作者：
Egami, Takuya;Ohuchida, Kenoki;Tanaka, Masao
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新途径。然而，目前还没有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，我们研究了化疗药物对腺病毒基因治疗转导效率的影响。表达NK4的腺病毒（Ad-NK4）作为肝细胞生长因子拮抗剂，被用作具有代表性的基因治疗。用化疗药物（5-氟尿嘧啶[5FU]、顺铂或依托泊苷）治疗感染Ad-NK4的胰腺癌细胞，测定其培养液中NK4水平。为了研究化疗药物在体内的作用，我们在化疗药物治疗小鼠皮下肿瘤后给药Ad-NK4，并测量肿瘤NK4的水平。5FU、顺铂和依托泊苷处理细胞培养液中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）。化疗药物也增加了Ad-NK4的摄取。5FU组、顺铂组和依托泊苷组NK4水平分别比未治疗组高5.4倍（P = 0.006）、11.8倍（P < 0.001）和4.9倍（P = 0.017）。本研究结果表明，化疗药物可显著提高腺病毒介导的胰腺癌基因转移的效率。此外，它们将有助于减少基因转移所需的腺病毒剂量，从而控制正常组织中腺病毒感染的副作用。（癌症科学2009；100:722-729）
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. (Cancer Sci 2009; 100: 722-729)