文章：

靶向缺氧癌症治疗

Targeting hypoxia in cancer therapy

原文发布日期：2011-05-24

DOI: 10.1038/nrc3064

类型: Review Article

开放获取: 否

要点：

1. Hypoxia represents a compelling therapeutic target, given that it has a major role in tumour development and resistance to therapy, and that the levels of hypoxia are more severe in most tumours than normal tissues.
2. One approach to targeting hypoxia seeks to develop bioreductive prodrugs that are activated by enzymatic reduction in hypoxic tissue. These prodrugs are chemically diverse and represent two distinct strategies: activation under moderate hypoxia (as exemplified by tirapazamine) or only under severe hypoxia (as exemplified by PR-104). In the latter case, diffusion of the active drug to less hypoxic cells is essential.
3. A second approach seeks small molecule inhibitors against molecular targets involved in the survival of hypoxic cells. Current interest focuses on the inhibition of the hypoxia-inducible factor 1 (HIF1), the unfolded protein response (UPR) and mTOR pathways, but the most important vulnerabilities in hypoxic cells are not well defined. Most molecularly targeted agents have been 'repurposed' from other applications, and have low selectivity as hypoxic cytotoxins.
4. Both approaches face substantial challenges in relation to off-target effects, which, ironically, also present opportunities. For bioreductive prodrugs, activation by aerobic reductases can contribute to normal tissue toxicity, but this is exploitable in tumours that highly express these enzymes. For molecularly targeted agents, hypoxia-independent signalling through the same pathways may provide opportunities for additional antitumour activity.
5. Both bioreductive prodrugs and molecularly targeted agents also need to overcome the problem of drug penetration through poorly perfused hypoxic tissue; strategies for addressing this requirement are being developed.
6. The current generation of bioreductive prodrugs generate DNA-reactive cytotoxins, making them difficult to combine with conventional chemotherapy because of overlapping toxicity. This challenge is stimulating the development of bioreductive prodrugs that release molecularly targeted agents as their effectors, potentially combining the best features of both approaches.
7. Given the marked heterogeneity in hypoxia between tumours of the same type, the clinical exploitation of hypoxia using all of these approaches will require their co-development with companion diagnostics for hypoxia (and for other determinants of sensitivity).

要点翻译：

1. 缺氧在肿瘤发展和治疗抵抗中起着重要作用，且大多数肿瘤中的缺氧程度比正常组织更为严重，这使其成为一个极具吸引力的治疗靶点。
2. 一种靶向缺氧的策略旨在开发生物还原性前体药物，这些药物可通过缺氧组织中的酶还原反应激活。这类前体药物具有化学多样性，代表两种不同策略：在中度缺氧条件下激活（以替拉扎明为例）或仅在严重缺氧条件下激活（以PR-104为例）。对于后者，活性药物向低氧细胞的扩散至关重要。
3. 第二种策略旨在开发针对缺氧细胞生存相关分子靶点的小分子抑制剂。当前研究重点集中于抑制缺氧诱导因子1（HIF1）、未折叠蛋白反应（UPR）和mTOR通路，但缺氧细胞中最关键的脆弱点尚未明确。大多数分子靶向药物是从其他应用“老药新用”而来，作为缺氧细胞毒素的选择性较低。
4. 两种策略都面临脱靶效应的重大挑战——具有讽刺意味的是，这同时也带来新的机遇。对于生物还原性前体药物，需氧还原酶的激活可能导致正常组织毒性，但在高表达这些酶的肿瘤中这一特性可被利用。对于分子靶向药物，相同通路的非缺氧依赖性信号传导可能为附加抗肿瘤活性提供机会。
5. 生物还原性前体药物和分子靶向药物均需解决药物在灌注不良的缺氧组织中渗透的问题，目前正在制定应对这一需求的策略。
6. 当前一代生物还原性前体药物会产生DNA反应性细胞毒素，由于与传统化疗存在毒性重叠，难以与之联用。这一挑战正推动着新型生物还原性前体药物的研发——这类药物能释放分子靶向药物作为效应器，有望结合两种策略的优势。
7. 鉴于同类型肿瘤间存在的显著缺氧异质性，在临床实践中利用所有这些缺氧靶向策略时，需要同步开发伴随性缺氧诊断技术（及其他敏感性决定因素的检测方法）。

英文摘要：

Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population. It is a negative prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism and genomic instability. Given its central role in tumour progression and resistance to therapy, tumour hypoxia might well be considered the best validated target that has yet to be exploited in oncology. However, despite an explosion of information on hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumour hypoxia is to be realized. Here, we review the two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting hypoxia.

摘要翻译： 

缺氧是大多数肿瘤的特征，尽管其在特定患者群体中的发生率和严重程度各异。由于其在化疗耐药、放疗耐药、血管生成、血管发生、侵袭性、转移、抗细胞死亡、代谢改变及基因组不稳定性等方面的多重作用，缺氧是一个负面的预后和预测因素。鉴于其在肿瘤进展和治疗耐药中的核心作用，肿瘤缺氧很可能被视为肿瘤学中尚未被利用的最佳验证靶点。然而，尽管关于缺氧的研究信息激增，若要实现长期以来的利用肿瘤缺氧的目标，仍有重大问待解决。在此，我们回顾了两种主要途径：即生物还原性前药和缺氧细胞存活所依赖的分子靶点抑制剂。我们探讨了这些重叠策略所带来的特殊挑战与机遇，并讨论了新兴诊断工具在缺氧靶向治疗中用于患者分层的关键重要性。

原文链接：

Targeting hypoxia in cancer therapy