Ayala Gustavo, Satoh Takefumi, Li Rile, Shalev Moshe, Gdor Yehoshua, Aguilar-Cordova Estuardo, Frolov Anna, Wheeler Thomas M, Miles Brian J, Rauen Kate, Teh Bin S, Butler E Brian, Thompson Timothy C, Kadmon Dov
Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Mol Ther. 2006 Apr;13(4):716-28. doi: 10.1016/j.ymthe.2005.11.022. Epub 2006 Feb 15.
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.
当前前列腺癌治疗方式的局限性促使研究人员寻找新的替代方法。此前我们发现前列腺癌中存在与单纯疱疹病毒胸苷激酶（HSV-tk）相关的细胞病变效应。在本研究中，我们展示了新辅助HSV-tk基因治疗试验的初步结果，并探讨了其在人体组织中作用的一些潜在机制方面。在这项I-II期试验中，我们招募了23名临床局限性前列腺癌但复发风险高的男性患者。进行前列腺内病毒注射（1至4次），随后给予2周的更昔洛韦，2 - 4周后进行前列腺切除术。毒性较小。将手术标本完全包埋，制作整装切片并成像，分析细胞病变效应区域。肿瘤越大，细胞病变效应越大。这种效应似乎也与高CAR表达区域有关。然而，注射部位的数量并不影响效果。接受HSV-tk治疗的患者局部（CD8 +细胞和巨噬细胞）和全身免疫反应（CD8 +和活化的CD8 +、IL-12）增强。这些患者还出现凋亡增加和微血管密度降低。结果表明存在由全身和局部免疫反应、抗血管生成作用以及凋亡调节介导的肿瘤特异性效应。
