Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours
Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours
复制标题
DOI：
10.1038/sj.gt.3301702
复制
发表时间：
2002-07-01
期刊：
影响因子：
5.1
通讯作者：
Stratford, IJ
中科院分区：
文献类型：
--
作者：
Patterson, AV;Williams, KJ;Stratford, IJ
大量的临床和实验数据表明，肿瘤缺氧与侵袭性疾病和不良治疗结果相关，因为缺氧细胞对放疗和某些形式的化疗无效。然而，缺氧在代表肿瘤特异性病症的生理正常组织中是罕见的。为了选择性地靶向这种治疗屈光细胞群，我们将生物还原性化疗与低氧导向的基因治疗相结合。我们已经转染了人纤维肉瘤细胞系，HT 1080，与缺氧调节的表达载体编码的人黄素蛋白细胞色素c P450还原酶（HRE-P450 R）。这在体外赋予了对烷基化硝基咪唑前药RSU 1069的缺氧依赖性敏感性，与对照相比，氧/缺氧细胞毒性比增加了30倍以上。HRE-P450 R和空载体转染子的异种移植物具有相当的缺氧分数，并且对高达15戈伊的单剂量放射治疗具有折射性。然而，将RSU 1069的前药与10戈伊的减少的放射治疗剂量组合代表HRE-P450 R异种移植物中的治愈性方案（50%无肿瘤存活;第100天）。完全相反，在以相同方式处理的空载体对照异种移植物中，到第44天100%死亡率是明显的。因此，氧敏感性基因导向的酶前药治疗方法在并入常规放疗和/或化疗方案中用于任何组织中的局部区域疾病时可能具有效用，其中缺氧是治疗成功的禁忌症。
Overwhelming clinical and experimental data demonstrate that tumour hypoxia is associated with aggressive disease and poor treatment outcome as hypoxic cells are refractive to radiotherapy and some forms of chemotherapy. However, hypoxia is rare in physiologically normal tissues representing a tumour-specific condition. To selectively target this therapeutically refractive cell population, we have combined bioreductive chemotherapy with hypoxia-directed gene therapy. We have transfected the human fibrosarcoma cell line, HT1080, with a hypoxia-regulated expression vector encoding the human flavoprotein cytochrome c P450 reductase (HRE-P450R). This conferred hypoxia-dependent sensitivity to the alkylating nitroimidazole prodrug RSU1069 in vitro, with a greater than 30-fold increase in oxic/hypoxic cytotoxicity ratio compared with controls. Xenografts of both the HRE-P450R and empty vector transfectants had comparable hypoxic fractions and were refractive to single dose radiotherapy of up to 15 Gy. However, combining a prodrug of RSU1069 with a reduced radiotherapy dose of 10 Gy represents a curative regimen (50% tumour-free survival; day 100) in the HRE-P450R xenografts, In complete contrast, 100% mortality was apparent by day 44 in the empty vector control xenografts treated in the same way. Thus, an oxygen-sensitive gene-directed enzyme prodrug therapy approach may have utility when incorporated into conventional radiotherapy and/or chemotherapy protocols for loco-regional disease in any tissue where hypoxia is a contra-indication to treatment success.