Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types.
Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types.
复制标题
逆转录病毒复制载体传递胞嘧啶脱氨酶，导致多种人类癌症类型中的靶向 5-氟尿嘧啶介导的细胞毒性。
DOI：
10.1089/hgtb.2015.106
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发表时间：
2016
影响因子：
--
通讯作者：
Derek Ostertag
中科院分区：
文献类型：
--
作者：
Christopher G. Twitty;Oscar R. Diago;Daniel J. Hogan;C. Burrascano;C. Ibañez;D. Jolly;Derek Ostertag
Toca 511是一种基于Moloney γ-逆转录病毒的改良逆转录病毒复制载体，具有嗜热性包膜。作为一种研究性癌症治疗，Toca 511优先感染癌细胞而不直接裂解细胞，并编码增强的酵母胞嘧啶脱氨酶，可将抗真菌药物5-氟胞嘧啶转化为抗癌药物5-氟尿嘧啶。一组已建立的人癌细胞系（来源于胶质母细胞瘤、结肠癌和乳腺癌组织）用于评价有效抗癌活性的关键参数。基因转移，胞嘧啶脱氨酶的生产，5-氟胞嘧啶转化为5-氟尿嘧啶，随后的细胞杀伤发生在所有测试线。我们在所有细胞系中观察到25天内>50%的感染，并且5-氟胞嘧啶LD 50值在0.02和6 μg/ml之间。尽管我们没有确定少数关键标准，但这些研究确实提供了一种直接的方法来快速评估Toca 511和5-氟胞嘧啶在各种癌症适应症中治疗效果的概率：最大感染癌细胞系的单次MTS试验，以确定5-氟胞嘧啶LD 50。数据表明，尽管由于多种机制因素，对Toca 511和5-氟胞嘧啶的敏感性可能存在差异，但该治疗可能适用于广泛的癌症类型和个体。
Toca 511 is a modified retroviral replicating vector based on Moloney γ-retrovirus with an amphotropic envelope. As an investigational cancer treatment, Toca 511 preferentially infects cancer cells without direct cell lysis and encodes an enhanced yeast cytosine deaminase that converts the antifungal drug 5-fluorocytosine to the anticancer drug, 5-fluorouracil. A panel of established human cancer cell lines, derived from glioblastoma, colon, and breast cancer tissue, was used to evaluate parameters critical for effective anticancer activity. Gene transfer, cytosine deaminase production, conversion of 5-fluorocytosine to 5-fluorouracil, and subsequent cell killing occurred in all lines tested. We observed >50% infection within 25 days in all lines and 5-fluorocytosine LD50 values between 0.02 and 6 μg/ml. Although we did not identify a small number of key criteria, these studies do provide a straightforward approach to rapidly gauge the probability of a Toca 511 and 5-fluorocytosine treatment effect in various cancer indications: a single MTS assay of maximally infected cancer cell lines to determine 5-fluorocytosine LD50. The data suggest that, although there can be variation in susceptibility to Toca 511 and 5-fluorocytosine because of multiple mechanistic factors, this therapy may be applicable to a broad range of cancer types and individuals.