Gene therapy approaches to enhance bioreductive drug treatment
Gene therapy approaches to enhance bioreductive drug treatment
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DOI：
10.1259/bjr/55070206
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发表时间：
2008-01-01
影响因子：
2.6
通讯作者：
Williams, K. J.
中科院分区：
文献类型：
--
作者：
Cowen, R. L.;Garside, E. J.;Williams, K. J.
缺氧或缺氧发生在50%-60%的实体人类肿瘤中。临床研究表明，肿瘤中缺氧的存在和程度不能通过肿瘤的大小或组织病理阶段来预测，但它可以预测放疗、化疗和手术后的不良结果。然而，作为肿瘤的一种生理特征，它可以被开发出来，研究人员已经开发了许多低氧选择性化疗或生物还原药物，这些药物正处于不同的临床开发阶段。这些药物是前体药物，它们的生物激活有两个关键要求：它们需要缺氧肿瘤细胞的还原环境和适当的细胞还原酶补充物。为了克服肿瘤还原酶水平的异质性，提高生物还原药物代谢，可以采用基因治疗策略。我们回顾了这一领域，并介绍了我们自己的临床前研究，使用基因疗法来加强生物还原药物治疗癌症的治疗。我们特别专注于加强铅临床生物还原药物的研究。我们考虑了它们激活的代谢要求，并重点介绍了支持低氧靶向基因导向酶前药治疗未来临床发展的关键体内研究。
Hypoxia, or a lack of oxygen, occurs in 50-60% of solid human tumours. Clinical studies have shown that the presence and extent of hypoxia in a tumour cannot be predicted by size or histopathological stage but it is predictive of a poor outcome following radiotherapy, chemotherapy and surgery. However, as a physiological feature of tumours, it can be exploited and researchers have developed many hypoxia-selective chemotherapies or bioreductive drugs that are in varying stages of clinical development. These agents are prodrugs that have two key requirements for their biological activation: they require the reductive environment of a hypoxic tumour cell and the appropriate complement of cellular reductase enzymes. To overcome tumour heterogeneity in reductase enzyme levels and enhance bioreductive drug metabolism a gene therapy strategy can be employed. We have reviewed this field and also present our own pre-clinical research using gene therapy to enhance bioreductive drug treatment for the treatment of cancer. We have specifically focused on studies enhancing lead clinical bioreductive drugs. We consider the metabolic requirements for their activation and we highlight the key in vivo studies supporting the future clinical development of hypoxia-targeted gene-directed enzyme prodrug therapy.