THE EXTENT OF HETEROCELLULAR COMMUNICATION MEDIATED BY GAP-JUNCTIONS IS PREDICTIVE OF BYSTANDER TUMOR-CYTOTOXICITY IN-VITRO
THE EXTENT OF HETEROCELLULAR COMMUNICATION MEDIATED BY GAP-JUNCTIONS IS PREDICTIVE OF BYSTANDER TUMOR-CYTOTOXICITY IN-VITRO
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DOI：
10.1073/pnas.92.24.11071
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发表时间：
1995-11-21
影响因子：
11.1
通讯作者：
ISRAEL, MA
中科院分区：
文献类型：
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作者：
FICK, J;BARKER, FG;ISRAEL, MA
单纯疱疹病毒胸苷激酶（HSV-tk）/更昔洛韦（GCV）病毒导向的酶前体药物基因治疗在动物模型中引起有效的肿瘤选择性细胞毒性，其中HSV-tk基因转导仅限于少数肿瘤细胞。在GCV治疗期间，毒性分子从HSV-tk（+）细胞传递到邻近的HSV-tk（-）细胞是可能解释这种“旁观者”细胞毒性的一种机制。为了研究间隙连接介导的细胞间偶联是否可以介导这种旁观者效应，我们使用流式细胞术测定HSV-tk（+）鼠成纤维细胞与啮齿动物和人肿瘤细胞系之间的异源细胞偶联程度。在共培养试验中，GCV治疗期间的旁观者肿瘤细胞毒性与间隙连接介导的偶联程度高度相关（P < 0.001）。这些发现表明，间隙连接介导的细胞间偶联有助于在体外旁观者效应在HSV-tk/GCV治疗和逆转录病毒转导的肿瘤细胞是不需要的旁观者细胞毒性。
Herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) viral-directed enzyme prodrug gene therapy causes potent, tumor-selective cytotoxicity in animal models in which HSV-tk gene transduction is limited to a minority of tumor cells. The passage of toxic molecules from HSV-tk(+) cells to neighboring HSV-tk(-) cells during GCV therapy is one mechanism that may account for this ''bystander'' cytotoxicity. To investigate whether gap junction-mediated intercellular coupling could mediate this bystander effect, we used a flow cytometry assay to quantitate the extent of heterocellular coupling between HSV-tk(+) murine fibroblasts and both rodent and human tumor cell lines. Bystander tumor cytotoxicity during GCV treatment in a coculture assay was highly correlated (P < 0.001) with the extent of gap junction-mediated coupling. These findings show that gap junction-mediated intercellular coupling contributes to the in vitro bystander effect during HSV-tk/GCV therapy and that retroviral transduction of tumor cells is not required for bystander cytotoxicity.