Yeast cytosine deaminase improves radiosensitization and bystander effect by 5-fluorocytosine of human colorectal cancer xenografts.
Yeast cytosine deaminase improves radiosensitization and bystander effect by 5-fluorocytosine of human colorectal cancer xenografts.
复制标题
DOI：
--
复制
发表时间：
2000-12
期刊：
影响因子：
11.2
通讯作者：
E. Kievit;M. Nyati;E. Ng;L. Stegman;J. Parsels;B. Ross;A. Rehemtulla;T. Lawrence
中科院分区：
文献类型：
--
作者：
E. Kievit;M. Nyati;E. Ng;L. Stegman;J. Parsels;B. Ross;A. Rehemtulla;T. Lawrence
使用细菌胞嘧啶脱氨酶 (bCD)/5-氟胞嘧啶 (5-FC) 酶/前药策略进行癌症基因治疗的功效受到胞嘧啶脱氨酶 (CD) 催化 5-FC 转化为 5-氟尿嘧啶 (5-FU) 效率低下的限制。我们之前已经证明，酵母 CD (yCD) 在 5-FC 转化方面比 bCD 更有效。在当前的研究中，我们假设yCD增加5-FU的产生将通过增加旁观者效应以及由于5-FU的放射增敏能力而提高放射治疗的功效来增强CD/5-FC治疗策略的功效。为了检验这一假设，我们生成了表达 bCD (HT29/bCD) 或 yCD (HT29/yCD) 的稳定 HT29 人结肠癌细胞系。单次注射 5-FC（1000 mg/kg，腹腔注射）后，HT29/yCD 肿瘤中产生的 5-FU 量比 HT29/bCD 肿瘤中产生的量高 15 倍。在荷瘤裸鼠中，经 5-FC 和放射治疗（腹腔注射 500 mg/kg 和 3 Gy，每周 5 天，持续 2 周）的 HT29/bCD 肿瘤的平均最小相对肿瘤大小（与治疗前值相比）为 0.55+/-0.1，而 HT29/yCD 肿瘤的平均最小相对肿瘤大小为 0.01+/-0.01（P = 0.002）。此外，当 HT29 细胞中表达 yCD 而不是 bCD 时，在体外和体内观察到 5-FC 对旁观者细胞的细胞毒性和放射增敏作用增加。在携带含有 10% HT29/yCD 细胞的 HT29 肿瘤的小鼠中，联合治疗导致最小肿瘤大小为 0.20+/-0.07，而 10% HT29/bCD 细胞的最小肿瘤大小为 0.60+/-0.1（P < 0.001）。这些结果表明，在 CD/5-FC 策略中使用 yCD 具有很大的潜力，可以改善癌症患者联合基因治疗和放射治疗的治疗结果。
The efficacy of cancer gene therapy using bacterial cytosine deaminase (bCD)/5-fluorocytosine (5-FC) enzyme/prodrug strategy is limited by the inefficiency of cytosine deaminase (CD)-catalyzed conversion of 5-FC into 5-fluorouracil (5-FU). We have shown previously that yeast CD (yCD) is more efficient at the conversion of 5-FC than bCD. In the current study, we hypothesized that the increased production of 5-FU by yCD would enhance the efficacy of the CD/5-FC treatment strategy by increasing the bystander effect as well as the efficacy of radiotherapy because of the radiosensitizing capacity of 5-FU. To test this hypothesis, we generated stable HT29 human colon cancer cell lines expressing either bCD (HT29/bCD) or yCD (HT29/yCD). The amount of 5-FU produced in HT29/yCD tumors after a single injection of 5-FC (1000 mg/kg, i.p.) was 15-fold higher than that produced in HT29/bCD tumors. In tumor-bearing nude mice, the average minimum relative tumor size (compared with pretreatment values) of HT29/bCD tumors treated with 5-FC and radiation (500 mg/kg i.p. and 3 Gy, 5 days a week for 2 weeks) was 0.55+/-0.1, compared with 0.01+/-0.01 in HT29/yCD tumors (P = 0.002). Moreover, an increased cytotoxic and radiosensitizing effect of 5-FC on bystander cells was observed in vitro and in vivo when yCD was expressed in HT29 cells instead of bCD. In mice bearing HT29 tumors containing 10% HT29/yCD cells, the combined treatment resulted in a minimum tumor size of 0.20+/-0.07 compared with 0.60+/-0.1 in 10% HT29/bCD cells (P < 0.001). These results demonstrate that the use of yCD in the CD/5-FC strategy has a high potential to improve the therapeutic outcome of combined gene therapy and radiotherapy in cancer patients.