Natural Plant Products Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, 176 061, India.
Curr Top Med Chem. 2012;12(13):1436-55. doi: 10.2174/156802612801784407.
Thalidomide and its one analogue, lenalidomide (CC5103 or revlimid) are recently approved for the treatment of multiple myeloma. Multiple myeloma is characterized by an overproduction of malignant plasma cells in the bone marrow. The journey of thalidomide was started in 1956 when it was marketed as a non-barbiturate sedative agent. It was considered as a "wonder drug" that provided safe and sound sleep and hence, used to cure morning sickness in pregnant women. Later, in 1961, it was withdrawn from the world market due to its serious side effects, i.e., teratogenic activity. However, the recent decade has witnessed a true renaissance in interest in its broad biological activity. In particular, thalidomide was reevaluated and attracted significant attention due to its selective inhibitory activity of tumor necrosis factor-α (TNF-α), which is a clinically important activity against serious diseases such as rheumatoid arthritis, Crohn's disease, leprosy, AIDS, and various cancers. The comeback of thalidomide to the legitimate status of a marketed drug came in 1998 when it received FDA approval for the treatment of erythema nodosum leprosum (ENL). Recently, the drug has got FDA approval for the treatment of multiple myeloma. In the last few years, number of thalidomide analogues have been synthesized and are in clinical development as a class of immunomodulatory drugs. Among these, lenalidomide is more potent than thalidomide, and is also non-neurotoxic. It was shown in vitro studies to induce apoptosis or arrest growth even in resistant multiple myeloma cell lines, decrease binding of the cells to bone marrow stromal cells, and stimulate host natural killer cell immunity. It also inhibits tumour growth and decreases angiogenesis. Earlier reviews have described the pharmacological aspects of thalidomide and a review has focused only on synthetic aspect of thalidomide. However, review focusing on chemistry and metabolism and mechanism of biological activity is still lacking. In this review, we will concisely describe the therapeutic aspects, metabolism and synthesis of thalidomide.
沙利度胺及其一种类似物来那度胺（CC5103 或雷利度胺）最近被批准用于治疗多发性骨髓瘤。多发性骨髓瘤的特征是骨髓中恶性浆细胞过度产生。沙利度胺的旅程始于 1956 年，当时它作为一种非巴比妥类镇静剂上市。它被认为是一种“神奇药物”，能提供安全而健康的睡眠，因此被用于治疗孕妇的晨吐。后来，它在 1961 年因严重的副作用（即致畸活性）从世界市场撤出。然而，在过去的十年中，它的广泛生物学活性再次引起了人们的兴趣。特别是，沙利度胺因其对肿瘤坏死因子-α（TNF-α）的选择性抑制活性而重新受到评估，并引起了广泛关注，因为这种活性对红斑狼疮、克罗恩病、麻风病、艾滋病和各种癌症等严重疾病具有重要的临床意义。沙利度胺于 1998 年重新获得合法上市药物的地位，获得 FDA 批准用于治疗结节性红斑狼疮（ENL）。最近，该药又获得 FDA 批准用于治疗多发性骨髓瘤。在过去的几年中，已经合成了许多沙利度胺类似物，并正在临床开发中作为一类免疫调节药物。其中，来那度胺比沙利度胺更有效，而且也没有神经毒性。体外研究表明，它甚至可以诱导耐药多发性骨髓瘤细胞系的细胞凋亡或生长停滞，减少细胞与骨髓基质细胞的结合，并刺激宿主自然杀伤细胞免疫。它还抑制肿瘤生长和减少血管生成。早期的综述描述了沙利度胺的药理学方面，而有一篇综述则专门关注沙利度胺的合成方面。然而，关于化学、代谢和生物学活性机制的综述仍然缺乏。在这篇综述中，我们将简明地描述沙利度胺的治疗方面、代谢和合成。
