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 1 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.