Kizaki Masahiro, Nakazato Tomonori, Ito Keisuke, Kawamura Chiharu, Miyakawa Yoshitaka, Ikeda Yasuo
Division of Hematology, Keio University School of Medicine, Tokyo, Japan.
Int J Hematol. 2002 Aug;76 Suppl 1:250-2. doi: 10.1007/BF03165253.
Hematological malignancies including acute leukemia, and multiple myeloma are disorders characterized by the accumulation of neoplastic hematopoietic cells, resulting in aggressive clinical manifestations with poor prognosis. The therapeutic approach to these disorders is basically chemotherapy for achieving complete remission based on the concept of total cell kill. However, severe side effects and complications such as serious infection and bleeding due to anti-cancer drugs are major problems in the clinical setting. In addition, repeated episodes of relapse of the disease may lead to refractory or chemotherapy-resistant disorders. These problems are occurred because anti-cancer agents have effects on both cancer cells and normal hematopoietic cells. The clinical evidences thus suggest the limitations of the chemotherapy for hematological malignancies: novel effective therapeutic approaches with less toxicity are therefore actively being sought. Differentiation-inducing therapy employing a physiologically active derivative of vitamin A, all-trans retinoic acid (ATRA), brought remarkably advances in the therapeutic outcome of APL at the end of last century. More recently, the clinical success of imatinib mesylate (STI571), potent competitive inhibitor of the Bcr/Abl protein tyrosine kinase, in the treatment of CML has focused enthusiasm toward molecular targeted therapy for the hematological malignancies. The therapeutic activity of these agents can be explained by their abilities to modify cellular growth, differentiation, and apoptosis in cells by activating unknown gene programs that molecular cellular proliferation. We have actively sought out new agents among natural products and cytokines with the ability to induce cellular differentiation and apoptosis. In this symposium, I will present our recent data of these novel compounds and their molecular mechanisms for inducing differentiation and apoptosis of hematological malignant cells.
血液系统恶性肿瘤，包括急性白血病和多发性骨髓瘤，其特征是肿瘤性造血细胞的积累，导致侵袭性临床表现且预后不良。针对这些疾病的治疗方法基本上是基于全细胞杀灭概念进行化疗以实现完全缓解。然而，抗癌药物引起的严重副作用和并发症，如严重感染和出血，是临床环境中的主要问题。此外，疾病的反复复发可能导致难治性或化疗耐药性疾病。这些问题的出现是因为抗癌药物对癌细胞和正常造血细胞都有作用。因此，临床证据表明血液系统恶性肿瘤化疗存在局限性：因此正在积极寻求毒性较小的新型有效治疗方法。上世纪末，使用维生素A的生理活性衍生物全反式维甲酸（ATRA）进行的诱导分化治疗在急性早幼粒细胞白血病的治疗结果方面取得了显著进展。最近，甲磺酸伊马替尼（STI571），一种Bcr/Abl蛋白酪氨酸激酶的强效竞争性抑制剂，在慢性粒细胞白血病治疗中的临床成功，使人们对血液系统恶性肿瘤的分子靶向治疗充满热情。这些药物的治疗活性可以通过它们激活分子细胞增殖的未知基因程序来调节细胞生长、分化和凋亡的能力来解释。我们一直在天然产物和细胞因子中积极寻找具有诱导细胞分化和凋亡能力的新药物。在本次研讨会上，我将展示我们关于这些新型化合物及其诱导血液系统恶性细胞分化和凋亡的分子机制的最新数据。
