Hattori Yutaka, Iguchi Toyotaka
Division of Hematology, Department of Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Congenit Anom (Kyoto). 2004 Sep;44(3):125-36. doi: 10.1111/j.1741-4520.2004.00025.x.
Although thalidomide was withdrawn in the 1960s after its teratogenic property was recognized, it was subsequently found that this drug possesses immunomodulatory and anti-inflammatory effects. Recent studies have also demonstrated that thalidomide has antineoplastic activity via an antiangiogenic mechanism. Observations in the late 1990s that the microenvironment in the bone marrow plays a role in tumor progression in multiple myeloma provided an impetus to use thalidomide for the treatment of this disease. It is known that thalidomide monotherapy is effective in one-third of refractory cases, and in combination with glucocorticoids and/or antineoplastic drugs, thalidomide provides a response rate of more than 50%. Thus, thalidomide therapy is considered a standard approach for the treatment of relapsed and refractory myeloma. The exact mechanism of the antimyeloma effect of thalidomide is not yet clearly understood. Anti-angiogenic effects, direct activity in tumor cells such as the induction of apoptosis or G1 arrest of the cell cycle, the inhibition of growth factor production, the regulation of interactions between tumor and stromal cells, and the modulation of tumor immunity have been considered as possible mechanisms. In addition to its teratogenicity, the adverse effects of thalidomide have been general symptoms such as somnolence and headache, peripheral neuropathy, constipation, skin rash, and other symptoms. Although these adverse effects are generally reversible and mild, grade 3 and 4 toxicities such as peripheral neuropathy, deep venous thrombosis, neutropenia, and toxic dermal necrosis have occasionally been reported. The application of thalidomide therapy in patients with multiple myeloma is being broadened to include not only cases of refractory myeloma, but also previously untreated cases, as well as for maintenance therapy after hematopoietic stem cell transplantation and for the treatment of other hematological diseases. The safe use of this drug will depend on the establishment of diagnostic and treatment guidelines. In addition, the establishment of a nation-wide regulation system is urgently needed in Japan.
尽管沙利度胺在20世纪60年代因其致畸特性被确认后就被撤市，但随后发现该药物具有免疫调节和抗炎作用。最近的研究还表明，沙利度胺通过抗血管生成机制具有抗肿瘤活性。20世纪90年代后期的观察发现，骨髓微环境在多发性骨髓瘤的肿瘤进展中起作用，这推动了将沙利度胺用于治疗该疾病。已知沙利度胺单药治疗对三分之一的难治性病例有效，并且与糖皮质激素和/或抗肿瘤药物联合使用时，沙利度胺的缓解率超过50%。因此，沙利度胺治疗被认为是复发和难治性骨髓瘤治疗的标准方法。沙利度胺抗骨髓瘤作用的确切机制尚未完全清楚。抗血管生成作用、在肿瘤细胞中的直接活性，如诱导细胞凋亡或使细胞周期停滞于G1期、抑制生长因子产生、调节肿瘤与基质细胞之间的相互作用以及调节肿瘤免疫，都被认为是可能的机制。除了致畸性外，沙利度胺的不良反应还有嗜睡、头痛等一般症状、周围神经病变、便秘、皮疹及其他症状。尽管这些不良反应通常是可逆且轻微的，但偶尔也有3级和4级毒性反应的报告，如周围神经病变、深静脉血栓形成、中性粒细胞减少和中毒性皮肤坏死。沙利度胺治疗在多发性骨髓瘤患者中的应用正在扩大，不仅包括难治性骨髓瘤病例，还包括既往未治疗的病例，以及造血干细胞移植后的维持治疗和其他血液系统疾病的治疗。该药物的安全使用将取决于诊断和治疗指南的建立。此外，日本迫切需要建立全国性的监管体系。
