Enhanced cytotoxicity with a novel system combining the paclitaxel-2′-ethylcarbonate prodrug and an HSV amplicon with an attenuated replication-competent virus, HF10 as a helper virus
Enhanced cytotoxicity with a novel system combining the paclitaxel-2′-ethylcarbonate prodrug and an HSV amplicon with an attenuated replication-competent virus, HF10 as a helper virus
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DOI：
10.1016/j.canlet.2009.06.014
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发表时间：
2010-02-01
期刊：
影响因子：
9.7
通讯作者：
Kikkawa, Fumitaka
中科院分区：
文献类型：
--
作者：
Ishida, Daisuke;Nawa, Akihiro;Kikkawa, Fumitaka
我们之前证明了HF10是一种自然的、非工程的HSV-1。在体外和体内实体恶性肿瘤的治疗中具有强大的溶瘤活性[H.Takakuwa，F.Goshima，N.Nozawa，T.Yoshikawa，H.Kimata，A.Nakao，等，使用自发产生的单纯疱疹病毒1型变种进行溶瘤病毒疗法，用于免疫活性小鼠播散性腹膜肿瘤，Arch。维罗尔。148(2003)813-825：S.Kohno，C.Lou，F.Goshima，Y.Nishiyama，T.Sata，Y.Ono，单纯疱疹病毒I型突变体HF10膀胱癌溶瘤病毒疗法，泌尿外科66(2005)1116-1121；D.渡边，F.Goshima，I.Mori，Y.Tamada，Y.MatSumoto，Y.Nishiyama，溶瘤病毒疗法对恶性黑色素瘤伴单纯疱疹病毒1型突变HF10，J.SCI。50(2008)185-196；A.Nawa，C.Luo，L.Zhang，Y.Ushijima，D.Ishida，M.Kamakura，等，非工程，自然溶瘤单纯疱疹病毒HSV1 HF10：应用于癌症基因治疗，Curr.吉恩。在那里。8(2008)208-221]。先前的报告也显示，对于某些类型的恶性肿瘤，HF10和紫杉醇(TAX)的联合应用比单独使用其中任何一种方案都更有效[S.Shimyama，F.Goshima，O.Teshigahara，H.Kasuya，Y.Kodera，A Nakao，等人，增强型单纯疱疹病毒突变株HF10与紫杉醇在腹膜癌扩散模型中的疗效，肝胃肠病学54(2007)1038-1042]。本研究将紫杉醇-2‘-乙基碳酸酯前药(TAX-2’-ET)和表达兔羧酸酯酶(CES)的单纯疱疹病毒(HSV)扩增子与HF10作为辅助病毒，研究了基因导向的酶前药疗法(GDEPT)的疗效。这种GDEPT系统的目的是在肿瘤部位产生高水平的CES，从而使Tax-2‘-ET前药有效地在局部转化为活性药物Tax[A.Nawa，T.Tanino，C.Lou，M.Iwaki，H.Kajiyama，K.Shibata等，GDEPT基因导向的酶前药治疗卵巢癌：GDEPT能否成为一种有前途的卵巢癌治疗方法？，AND Chem 8(2008)232-239]。我们证明了作为示踪标记的绿色荧光蛋白(GFP)基因，与表达载体PHGCX相比，HSV扩增系统在COS7细胞中表达了能将TAX-2‘-ET转化为TAX的活性CES酶。此外，尽管该扩增系统在病毒敏感的肿瘤细胞中的细胞毒性没有增强，但在低病毒敏感的肿瘤细胞中，该扩增子系统的细胞毒性在前药物存在下以浓度依赖的方式显著增强，与对照病毒单独作用相比(p<；0.05)。这些结果表明，添加前药物转换酶可能是进一步提高HF10作为癌症治疗药物对低HF10敏感的恶性肿瘤的一种可行的方法。(C)2009爱思唯尔爱尔兰有限公司。保留所有权利。
We previously demonstrated that HF10, which is a natural, non-engineered HSV-1. has potent oncolytic activity in the treatment of solid malignant tumors in vitro and in vivo [H. Takakuwa, F. Goshima, N. Nozawa, T. Yoshikawa, H. Kimata, A. Nakao, et al., Oncolytic viral therapy using a spontaneously generated herpes simplex virus type 1 variant for disseminated peritoneal tumor in immunocompetent mice, Arch. Virol. 148 (2003) 813-825: S. Kohno, C. Lou, F. Goshima, Y. Nishiyama, T. Sata, Y. Ono, Herpes simplex virus type I mutant HF10 oncolytic viral therapy for bladder cancer, Urology 66 (2005) 1116-1121; D. Watanabe, F. Goshima, I. Mori, Y. Tamada, Y. Matsumoto, Y. Nishiyama, Oncolytic virotherapy for malignant melanoma with herpes simplex virus type 1 mutant HF10,J. Dermatol. Sci. 50 (2008) 185-196; A. Nawa, C. Luo, L. Zhang, Y. Ushijima, D. Ishida, M. Kamakura, et al., Non-engineered, naturally oncolytic herpes simplex virus HSV1 HF10: applications for cancer gene therapy, Curr. Gene. Ther. 8 (2008) 208-221]. Previous reports have also shown that a combination of HF10 and paclitaxel (TAX) was more efficacious than either regimen alone for some types of malignant tumors [S. Shimoyama, F. Goshima, O. Teshigahara, H. Kasuya, Y. Kodera, A Nakao, et al., Enhanced efficacy of herpes simplex virus mutant HF10 combined with paclitaxel in peritoneal cancer dissemination models, Hepatogastroenterology 54 (2007) 1038-1042]. In this study, we investigated the efficacy of gene-directed enzyme prodrug therapy (GDEPT) using a novel system that combines the paclitaxel-2'-ethylcarbonate prodrug (TAX-2'-Et) and an HSV amplicon expressing rabbit-carboxylesterase (CES) with HF10 as a helper virus. This GDEPT system aims to produce high level of CES at the tumor site, resulting in efficient local conversion of the TAX-2'-Et prodrug into the active drug TAX [A. Nawa, T. Tanino, C. Lou, M. Iwaki, H. Kajiyama, K. Shibata, et al., Gene directed enzyme prodrug therapy for ovarian cancer: could GDEPT become a promising treatment against ovarian cancer?, Anti-Cancer Agents Med Chem 8 (2008)232-239].We demonstrated that the green fluorescent protein (GFP) gene, as a trace maker, was more efficiently introduced by the HSV amplicon compared to the expression vector, pHGCX, and that the HSV amplicon system expressed an active CES enzyme that could convert TAX-2'-Et to TAX in Cos7 cells. Furthermore, although the cytotoxicity of this amplicon system was not enhanced in virus-sensitive tumor cells, it was significantly enhanced in low virus-sensitive tumor cells in the presence of the prodrug in a concentration-dependent manner, compared to the control virus alone (p < 0.05).These results indicate that the addition of a prodrug converting enzyme may be a feasible approach to further enhance the efficacy of HF10 as a cancer therapeutics in low HF10-sensitive malignancies. (C) 2009 Elsevier Ireland Ltd. All rights reserved.