SELECTIVE ENHANCEMENT OF RADIATION RESPONSE OF HERPES-SIMPLEX VIRUS THYMIDINE KINASE TRANSDUCED 9L GLIOSARCOMA CELLS IN-VITRO AND IN-VIVO BY ANTIVIRAL AGENTS
SELECTIVE ENHANCEMENT OF RADIATION RESPONSE OF HERPES-SIMPLEX VIRUS THYMIDINE KINASE TRANSDUCED 9L GLIOSARCOMA CELLS IN-VITRO AND IN-VIVO BY ANTIVIRAL AGENTS
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DOI：
10.1016/0360-3016(95)00134-9
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发表时间：
1995-11-01
影响因子：
7
通讯作者：
FREYTAG, SO
中科院分区：
文献类型：
--
作者：
KIM, JH;KIM, SH;FREYTAG, SO
目的：为了在充分表征的肿瘤模型中证明，用单纯疱疹病毒胸苷激酶基因（HS-tk）转导的肿瘤细胞的放射敏感性将被抗病毒剂选择性地增强。用含有HS-tk基因的逆转录病毒载体转导大鼠9 L胶质肉瘤细胞，将PL-tk细胞在体外或体内条件下暴露于各种剂量的辐射，本文报道了两种抗病毒药物溴乙烯脱氧尿苷（BVdU）和二羟甲基乙基甲基鸟嘌呤（Acyclovir）的体外放射增敏作用，并以大鼠脑内生长的9 L-tk肿瘤为模型，评价了BVdU的放射增敏作用。对生长在大鼠大脑右半球的肿瘤进行单剂量立体定向照射。9 L-tk细胞的辐射反应被抗病毒药物选择性地增强，相对于未转导的细胞，在细胞培养中，当24小时的药物暴露时，（20 μ g/ml），BVdU和阿昔洛韦的增敏率（SER）分别为1.4 +/- 0.1和1.3 +/- 0.1，将细胞暴露于10 μ g/ml无环鸟苷两个24小时的时间段，辐射前和辐射后均导致SER为1.6 +/-0.1。当在单次给药前给予BVdU时，发现患有9 L-tk肿瘤的大鼠的中位存活时间显著增加，剂量照射相对于单独接受辐射的类似大鼠的存活时间。一种抗病毒剂可以增强辐射对转导了单纯疱疹病毒胸苷激酶基因的细胞的杀伤作用，全身施用抗病毒药物和立体定向靶向放射治疗将提高放射治疗用于治疗放射抗性肿瘤的有效性。
Purpose: To demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents.Methods and Materials: Rat 9L, gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, PL-tk cells were exposed to various doses of irradiation under either in vitro or in vivo conditions, The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro, The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation.Results: The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells, In the cell culture, when a 24-h drug exposure (20 mu g/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 +/- 0.1 and 1.3 +/- 0.1, respectively, Exposure of cells to 10 mu g/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 +/- 0.1, In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone.Conclusion: An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene, The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors.