The promise of anti-angiogenic cancer therapy.
The promise of anti-angiogenic cancer therapy.
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DOI：
10.1054/bjoc.1999.0991
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发表时间：
2000-02
影响因子：
8.8
通讯作者：
Bicknell R
中科院分区：
文献类型：
--
作者：
Oehler MK;Bicknell R
一年前，《纽约时报》（Kolata，1998）的一篇头版文章引发了人们的猜测，认为可以用血管抑制素和内皮抑制素治疗癌症。这篇文章以及其他媒体的报道引起了公众对血管生成抑制剂的强烈兴趣，并引发了随后的争议和情绪化辩论（Wadman，1998; Cohen，1999; Harris，1999; Rowe，1999）。波士顿以外的实验室对内皮抑制素的研究无法证实内皮抑制素的结果，仅显示小鼠刘易斯肺癌（一种难以用化疗药物治疗的肿瘤）的轻微生长迟缓，这引发了争议。NCI的成员前往波士顿的Folkman实验室，澄清为什么结果与原始研究中的结果不同。在波士顿，随后的结果与之前的实验一致，显示出对肿瘤生长的显著抑制。两个实验室之间实验技术的差异，如注射小鼠，以及内皮抑制素的储存、处理和纯化，被认为是先前观察到的结果不一致的原因。NCI在小鼠内皮抑制素上的成功--仅仅在它被公开宣布无法复制结果的几个月后--允许该研究所启动在患者中测试人类内皮抑制素的计划，等待全面的毒理学研究。1999年初秋，预计两个地点将进行第一阶段研究，每个地点约有15-25名实体瘤患者，包括肺癌、乳腺癌、结肠癌和前列腺癌。为了开展临床研究，有必要扩大内皮抑制素的生产。通过应用酵母表达系统，现在可以产生足以在人体中进行临床评估的量的可溶性人内皮抑制素（Sim等，1999）。到目前为止，血管抑素和内皮抑素的动物研究仅针对移植肿瘤，与器官特异性自发性肿瘤相比，移植肿瘤显示出不同的生物学特性，并且不一定是自然人类癌症中发生的准确预测因子。因此，使用胰岛癌发生的转基因小鼠模型（RIP 1-Tag 2）作为模型来检查几种血管生成抑制剂对多阶段肿瘤发生的作用（Bergers等人，1999）。除了内皮抑制素、血管抑制素和两者的组合之外，还测试了AGM-1470（TNP 470;一种烟曲霉素衍生物，其被认为通过与甲硫氨酰氨基肽酶-2的不可逆结合来抑制内皮细胞增殖）（Sin等人，1997）和BB-94（巴马司他;一种基质金属蛋白酶抑制剂）（塔尔博特和Brown，1996）的它们的生物学活性。
One year ago, a front page article in the New York Times (Kolata, 1998) initiated speculation that cancer could be treated with angiostatin and endostatin. That article, and coverage by other media, generated intense public interest in angiogenesis inhibitors and a subsequent controversial and emotional debate (Wadman, 1998; Cohen, 1999; Harris, 1999; Rowe, 1999). The controversy was fueled as studies on endostatin in laboratories outside Boston were unable to confirm the endostatin results, showing only a slight growth retardation of Lewis lung carcinoma (a difficult tumour to treat with chemotherapeutic agents) in mice. Members of the NCI went to Folkman’s laboratory in Boston to clarify why the results differed from those in the original study. In Boston, subsequent results were consistent with previous experiments, showing striking inhibition of tumour growth. Variations in experimental techniques between the two laboratories, such as injecting mice, as well as storage, handling and purification of endostatin, are assumed to have been responsible for the previously observed lack of agreement in results. The NCI’s success with mouse endostatin–just a few months after it had been announced publicity that it could not replicate the results–allowed the Institute to initiate plans for the testing of human endostatin in patients, pending full-scale toxicology studies. In early fall of 1999 two sites were expected to conduct phase I studies with approximately 15–25 patients each in patients with solid tumours, including lung, breast, colon and prostate carcinoma. To launch clinical studies it has been necessary to scale up the production of endostatin. By applying a yeast expression system it is now possible to produce soluble human endostatin at quantities sufficient for clinical assessment in man (Sim et al, 1999). Animal studies with angiostatin and endostatin have so far been only with transplanted tumours, which show a different biology when compared to organ-specific, spontaneous tumours and are not necessarily accurate predictors of what will happen in natural human cancers. Thus, a transgenic mouse model of pancreatic islet carcinogenesis (RIP1-Tag2) was used as a model to examine the effect of several angiogenesis inhibitors on multistage tumorigenesis (Bergers et al, 1999). Apart from endostatin, angiostatin and a combination of both, AGM-1470 (TNP470; a fumagillin derivative which is thought to inhibit endothelial cell proliferation by irreversible binding to the enzyme methionylaminopeptidase-2)(Sin et al, 1997) and BB-94 (batimastat; a matrix metalloproteinases inhibitor)(Talbot and Brown, 1996) were tested for their