文章目录

利用肿瘤缺氧治疗癌症

Exploiting tumour hypoxia in cancer treatment

原文发布日期：2004-06-01

DOI: 10.1038/nrc1367

类型: Review Article

开放获取: 否

要点：

要点翻译：

英文摘要：

摘要翻译：

原文链接：

文章：

利用肿瘤缺氧治疗癌症

Exploiting tumour hypoxia in cancer treatment

原文发布日期：2004-06-01

DOI: 10.1038/nrc1367

类型: Review Article

开放获取: 否

要点：

A characteristic feature of solid tumours is the presence of cells at very low oxygen tensions. These hypoxic cells confer radiotherapy and chemotherapy resistance to the tumours, as well as selecting for a more malignant phenotype.
These hypoxic cells, however, provide a tumour-specific targeting strategy for therapy, and four approaches are being investigated: prodrugs activated by hypoxia; hypoxia-selective gene therapy; targeting the hypoxia-inducible factor 1 (HIF-1) transcription factor; and the use of recombinant obligate anaerobic bacteria.
Tirapazamine is the prototype hypoxia-activated prodrug. Its toxic metabolite, a highly reactive radical that is present at higher concentrations under hypoxia, selectively kills the resistant hypoxic cells in tumours. This makes the tumours much more sensitive to treatment with conventional chemotherapy and radiotherapy.
Several other hypoxia-activated prodrugs, including AQ4N, NLCQ-1 and dinitrobenzamide mustards, are in preclinical or early clinical development.
Hypoxia-activated gene therapy using hypoxia-specific promoters provides selective transcription of enzymes that can convert prodrugs into toxic drugs. The efficacy of this approach has been shown in animal models, but clinical testing must await better systemic delivery of vectors to hypoxic cells.
Targeting HIF-1 is a third strategy. This protein is stabilized under hypoxic conditions and promotes the survival of tumour cells under hypoxic conditions. Several strategies to inactivate or to exploit this unique protein in tumours are being investigated at the preclinical level.
Finally, using recombinant non-pathogenic clostridia — an obligate anaerobe that colonizes tumour necrosis after systemic administration — is another strategy to exploit the unique physiology of solid tumours. This approach has demonstrated considerable preclinical efficacy.

要点翻译：

实体肿瘤的一个典型特征是存在处于极低氧张力下的细胞。这些缺氧细胞不仅使肿瘤对放疗和化疗产生抵抗，还会筛选出恶性程度更高的表型。
然而，这些缺氧细胞为治疗提供了肿瘤特异性靶向策略，目前正在研究四种方法：缺氧激活的前体药物；缺氧选择性基因疗法；靶向缺氧诱导因子1（HIF-1）转录因子；以及使用重组专性厌氧菌。
替拉扎明是缺氧激活前体药物的原型。其毒性代谢物是一种高活性自由基，在缺氧条件下浓度更高，能选择性杀伤肿瘤中耐药的缺氧细胞。这使得肿瘤对常规化疗和放疗的敏感性显著增强。
其他几种缺氧激活前体药物（包括AQ4N、NLCQ-1和二硝基苯酰胺芥子类化合物）正处于临床前或早期临床开发阶段。
利用缺氧特异性启动子的缺氧激活基因疗法，可实现能将前体药物转化为毒性药物的酶的选择性转录。该方法在动物模型中已显示疗效，但临床测试需待载体能更有效地全身递送至缺氧细胞。
靶向HIF-1是第三种策略。该蛋白在缺氧条件下稳定存在，并能促进肿瘤细胞在缺氧环境下的存活。目前正在临床前层面研究几种灭活或利用该独特蛋白的策略。
最后，使用重组非致病性梭菌（一种经全身给药后定植于肿瘤坏死区的专性厌氧菌）是利用实体瘤独特生理特性的另一策略。该方法已在临床前研究中展现出显著疗效。

英文摘要：

Solid tumours contain regions at very low oxygen concentrations (hypoxia), often surrounding areas of necrosis. The cells in these hypoxic regions are resistant to both radiotherapy and chemotherapy. However, the existence of hypoxia and necrosis also provides an opportunity for tumour-selective therapy, including prodrugs activated by hypoxia, hypoxia-specific gene therapy, targeting the hypoxia-inducible factor 1 transcription factor, and recombinant anaerobic bacteria. These strategies could turn what is now an impediment into a significant advantage for cancer therapy.