Biological response determinants in HSV-tk plus ganciclovir gene therapy for prostate cancer

被引:49
作者
Ayala, G
Satoh, T
Li, R
Shalev, M
Gdor, Y
Aguilar-Cordova, E
Frolov, A
Wheeler, TM
Miles, BJ
Rauen, K
Teh, BS
Butler, EB
Thompson, TC
Kadmon, D
机构
[1] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Urol, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Mol & Cell Biol, Houston, TX 77030 USA
[5] Univ Calif San Francisco, Canc Res Inst, Ctr Comprehens Canc, San Francisco, CA 94143 USA
关键词
gene therapy; HSV-tk; prostate cancer; immune response; microvessel density; necrosis; apoptosis; car;
D O I
10.1016/j.ymthe.2005.11.022
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The limitations of current forms of prostate cancer therapy have driven researchers to search for new alternatives. Previously we showed cytopathic effect related to HSV-tk in prostate cancer. In this study we present initial results of a neoadjuvant HSV-tk gene therapy trial and address some of the potential mechanistic aspects of its effect in human tissues. We enrolled 23 men with clinically localized prostate cancer but high risk for recurrence in this Phase I-II trial. Intraprostatic viral injections (one to four) were followed by 2 weeks of ganciclovir and prostatectomy 2-4 weeks later. Toxicity was modest. Surgical specimens were embedded fully and whole-mount slides were imaged and analyzed for areas of cytopathic effect. The larger the tumor the greater the cytopathic effect. The effect also seems to be related to areas of high CAR expression. However, the number of injection sites did not influence effect. Local (CD8(+) cells and macrophages) and systemic immune response (CD8(+) and activated CD8(+), IL-12) was increased in patients treated with HSV-tk. Increased apoptosis and decreased microvessel density were also noted in these patients. The results suggest a tumor-specific effect mediated by systemic and local immune response, antiangiogenic effect, and modulation of apoptosis.
引用
收藏
页码:716 / 728
页数:13
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