Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas.
Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas.
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发表时间：
2002-02
期刊：
影响因子：
11.2
通讯作者：
C. Miller;C. Williams;D. Buchsbaum;G. Gillespie
中科院分区：
文献类型：
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作者：
C. Miller;C. Williams;D. Buchsbaum;G. Gillespie
5-氟尿嘧啶 (5-FU) 是一种有效的抗代谢药物，用于胃肠道 (GI)、乳腺癌和头颈恶性肿瘤的化疗。尽管已经进行了临床试验，但 5-FU 较差的治疗指数阻碍了其在许多其他肿瘤类型的临床应用。目前尚不清楚这种实用性的缺乏是否是由于药物输送问题或固有的不敏感性造成的。腺病毒 (Ad) 载体介导的胞嘧啶脱氨酶 (CD)/5-氟胞嘧啶 (5-FC) 基因治疗有可能克服与全身 5-FU 相关的药代动力学问题，特别适合用于局部控制至关重要的肿瘤，例如复发性局限性前列腺癌和恶性神经胶质瘤。在这项研究中，检查了一组源自胃肠道（结肠、胰腺）和非胃肠道（前列腺、神经胶质瘤）肿瘤的人类肿瘤细胞系对 5-FU 和 AdCMVCD（编码大肠杆菌 CD 的 Ad）/5-FC 的体外反应。尽管各个细胞系对这些药物的敏感性 (IC(50)) 各不相同，但对于所测试的四种肿瘤类型，5-FU 或 AdCMVCD/5-FC 的中值 IC(50) 没有明显差异 (P > 0.1)。然后评估了 Ad 基因转移效率和固有 5-FU 敏感性在确定 AdCMVCD/5-FC 反应中的相关贡献。多元线性回归分析显示，虽然这两个因素对反应都有显着影响，但固有的 5-FU 敏感性更为重要（β= 0.78 与 0.48；P < 0.001）。最后，在三个颅内 C.B17 严重联合免疫缺陷小鼠模型中评估了单次瘤内注射 AdCMVCD 随后全身注射 5-FC 的治疗效果。 AdCMVCD/5-FC 功效具有特异性、病毒剂量依赖性，并且在所测试的三个模型中的两个模型中与体外 5-FU 和 CD/5-FC 敏感性密切相关。这些结果表明，神经胶质瘤细胞与胃肠道肿瘤细胞一样对 5-FU 的抗肿瘤作用敏感，将固有的 5-FU 敏感性确定为决定 CD/5-FC 疗效的重要因素，并证实了先前在大鼠模型中的发现，证明了 AdCMVCD/5-FC 基因治疗对神经胶质瘤的潜在临床效用。
5-Fluorouracil (5-FU) is a potent antimetabolite used for chemotherapy of gastrointestinal (GI), breast, and head and neck malignancies. Although clinical trials have been conducted, the poor therapeutic index of 5-FU has precluded its clinical use for a number of other tumor types. It is unclear whether this lack of utility is due to problems with drug delivery or inherent insensitivity. Adenovirus (Ad) vector-mediated cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy has the potential to overcome pharmacokinetic issues associated with systemic 5-FU and is particularly well suited to use with tumors in which local control is paramount, such as recurrent, localized prostate cancer and malignant gliomas. In this study, the in vitro response by a panel of human tumor cell lines derived from both GI (colon, pancreas) and non-GI (prostate, glioma) tumors to 5-FU and to AdCMVCD (an Ad encoding Escherichia coli CD)/5-FC was examined. Whereas the sensitivity (IC(50)) of individual cell lines to these agents varied, no significant difference in median IC(50) for either 5-FU or AdCMVCD/5-FC was evident for the four tumor types tested (P > 0.1). The relevant contributions of Ad gene transfer efficiency and inherent 5-FU sensitivity in determining response to AdCMVCD/5-FC were then assessed. Multiple linear regression analysis revealed that whereas both factors significantly contribute to the response, inherent 5-FU sensitivity was substantially more important (beta= 0.78 versus 0.48; P < 0.001). Finally, the therapeutic efficacy of a single intratumoral injection of AdCMVCD followed by systemic 5-FC was assessed in three intracranial C.B17 severe combined immunodeficient mouse models of human glioma. AdCMVCD/5-FC efficacy was specific, virus dose-dependent, and closely paralleled in vitro 5-FU and CD/5-FC sensitivity in two of three models tested. These results reveal that glioma cells are as sensitive as GI tumor cells to the antineoplastic effects of 5-FU, identify inherent 5-FU sensitivity as an important factor in determining CD/5-FC efficacy, and confirm previous findings in rat models that demonstrate the potential clinical utility of AdCMVCD/5-FC gene therapy for gliomas.