Long-term treatment with valganciclovir improves lentiviral suicide gene therapy of glioblastoma
Long-term treatment with valganciclovir improves lentiviral suicide gene therapy of glioblastoma
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DOI：
10.1093/neuonc/noz060
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发表时间：
2019-07-01
期刊：
影响因子：
15.9
通讯作者：
Miletic, Hrvoje
中科院分区：
文献类型：
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作者：
Hossain, Jubayer A.;Latif, Md A.;Miletic, Hrvoje
背景恶性胶质瘤的自杀基因治疗在最新的临床试验中显示出令人鼓舞的结果。然而，前体药物的应用通常限于短期治疗(14天)，特别是当使用复制缺陷载体时。我们以前发现，在原位胶质母细胞瘤(GBM)异种移植模型中，相当一部分转导单纯疱疹病毒胸苷激酶(HSV-TK)的肿瘤细胞在更昔洛韦(GCV)治疗下存活。方法从自杀基因治疗后复发的异种移植瘤中分离出TK和绿色荧光蛋白(GFP)阳性的胶质瘤细胞，体外检测其对GCV的敏感性。用HSV-TK/GCV、HSV-TK/valganciclovir(ValGCV)或HSV-TK/valGCV+erlotinib治疗GBM移植瘤。结果TK-GFP+肿瘤细胞在体外对GCV仍具有敏感性。重要的是，与短期(3wk)应用Valganciclovir(ValGCV)相比，较长时间(3mo)使用valganciclovir(ValGCV)可获得显著的生存优势。与原发肿瘤相比，治疗组复发肿瘤侵袭性更强，血管生成更少，表皮生长因子受体(EGFR)表达显著上调。结论在HSV-TK介导的自杀基因治疗的临床试验中，长期应用valGCV可替代短期应用GCV。
Background Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to short-term treatment (14 days), especially when replication-defective vectors were used. We previously showed that a substantial fraction of herpes simplex virus thymidine kinase (HSV-TK) transduced tumor cells survive ganciclovir (GCV) treatment in an orthotopic glioblastoma (GBM) xenograft model. Here we analyzed whether these TK+ tumor cells are still sensitive to prodrug treatment and whether prolonged prodrug treatment can enhance treatment efficacy.Methods Glioma cells positive for TK and green fluorescent protein (GFP) were sorted from xenograft tumors recurring after suicide gene therapy, and their sensitivity to GCV was tested in vitro. GBM xenografts were treated with HSV-TK/GCV, HSV-TK/valganciclovir (valGCV), or HSV-TK/valGCV + erlotinib. Tumor growth was analyzed by MRI, and survival as well as morphological and molecular changes were assessed.Results TK-GFP+ tumor cells from recurrent xenograft tumors retained sensitivity to GCV in vitro. Importantly, a prolonged period (3 mo) of prodrug administration with valganciclovir (valGCV) resulted in a significant survival advantage compared with short-term (3 wk) application of GCV. Recurrent tumors from the treatment groups were more invasive and less angiogenic compared with primary tumors and showed significant upregulation of epidermal growth factor receptor (EGFR) expression. However, double treatment with the EGFR inhibitor erlotinib did not increase therapeutic efficacy.Conclusion Long-term treatment with valGCV should be considered as a replacement for short-term treatment with GCV in clinical trials of HSV-TK mediated suicide gene therapy.