Role of various carotenoids in lung cancer prevention
Role of various carotenoids in lung cancer prevention
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DOI：
10.1093/jnci/91.2.182
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发表时间：
1999-01-20
期刊：
影响因子：
--
通讯作者：
Seppänen, R
中科院分区：
文献类型：
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作者：
Knekt, P;Järvinen, R;Seppänen, R
大多数研究人员会同意，理想的化疗药物应该是1)针对已确认的靶点；2)有效，最好是在纳摩尔或亚纳摩尔浓度下有效；3)独立于程序，甚至在非周期细胞中有效；4)对耐药细胞有效；以及5)对正常细胞毒性较小或理想情况下无毒。在本期杂志中，Leoni等人(1)建议吲哚可辛，一种合成的抗有丝分裂吲哚酮，具有所有这些性质。要令人信服地证明这一点，还需要进一步的研究，但即使吲哚可卡因不是理想的化合物，最终也可能找到或合成一种化合物。抗分裂药物包括一组不同的化合物，其中大多数是天然产物，其不同的作用机制导致共同的终点：有丝分裂停止(2，3)。这些药物中的大多数通过与微管蛋白相互作用而诱导有丝分裂停止，最简单的分类将这些药物分为解聚微管蛋白的药物和稳定微管蛋白聚合物的药物。解聚剂进一步细分为与长春花碱结合位点相互作用的解聚剂和以秋水仙素结合位点为靶点的解聚剂，秋水仙素是包括吲哚类化合物的一组。微管蛋白的聚合剂包括紫杉烷类、环氧丙酮类、盘状分子和肌动蛋白/血凝素类化合物(2-5)。这些试剂的靶标是微管的基本亚基微管蛋白，也是进化过程中高度保守的蛋白质之一(6，7)。作为一个整体，这些药物在治疗癌症方面取得了如此成功，因此没有人会质疑微管蛋白是一个有效的靶点。事实上，考虑到紫杉烷的广泛活性和长春花碱的实用性，可以说微管蛋白是迄今为止确定的最好的靶标(8)。这并不令人惊讶，因为大多数已知的抗有丝分裂药物都是天然产品或其衍生物，从海洋和陆地的许多种类的生物中获得，从蓝藻到哺乳动物。有人可能会争辩说，微管蛋白作为一个靶子，已经一次又一次地得到了“大自然”的验证(2)。
Most investigators would agree that the ideal chemotherapeutic agent should be 1) directed at a validated target; 2) potent, preferably active at nanomolar or subnanomolar concentrations; 3) schedule independent, even active in noncycling cells; 4) active against drug-resistant cells; and 5) less toxic or ideally not toxic to normal cells. In this issue of the Journal, Leoni et al.(1) suggest that indanocine, a synthetic antimitotic indanone, possesses all of these properties. Further studies will be needed to prove this convincingly, but even if indanocine is not the ideal compound, one may eventually be found or synthesized. The antimitotic drugs include a diverse group of compounds, most of which are natural products, whose varied mechanisms of action result in a common end point: mitotic arrest (2, 3). The majority of these agents induce mitotic arrest by interacting with tubulin, and the simplest classification divides these agents into those that depolymerize tubulin and those that stabilize tubulin polymers. Depolymerizing agents are further subclassified into those that interact with the vinca binding site and those that target the colchicine site, a group that includes the indanones. Agents that polymerize tubulin include the taxanes, the epothilones, discodermolide, and the sarcodyctin/eleutherobin class of compounds (2–5).The target for these agents is tubulin, the basic subunit of microtubules and one of the most highly conserved proteins in evolution (6, 7). As a group, these agents have been so successful in the treatment of cancer that no one would dispute that tubulin is a valid target. Indeed, given the widespread activity of the taxanes and the utility of the vincas, it could be argued that tubulin represents the single best target identified to date (8). This should not be surprising, since the majority of known antimitotic agents are natural products, or derivatives thereof, and have been obtained from many classes of organisms, marine and terrestrial, from Cyanobacteria to mammals. One could argue that tubulin, as a target, has been validated time and again by “Mother Nature”(2).