Differentiation therapy of acute promylocytic leukemia.

本次合作项目的合作伙伴王振中教授等人。1998年，上海第二医学院在世界上首次报道了维生素A的活性形式全反式维甲酸(ATRA)作为一种分化疗法，对急性早幼粒细胞白血病(APL)有93%的完全缓解率(CR)。1960年召开日中血液学学会联席会议后，我们启动了全反式维甲酸(ATRA)治疗化疗难治性APL的工作，并证实其对APL的疗效显著。目前，超过60%的初诊APL患者被ATRA及随后的化疗治愈。本课题主要从分子生物学的角度探讨ATRA对APL的作用机制。我们不仅交流了这方面的知识和信息，还交流了两国患者的APL细胞和我们实验室研制的针对APL白血病发生相关基因产物PML蛋白的单抗等材料。我们还交换了一种新的有前景的治疗方法的最新信息，使用As_2O_3是一种抗白血病中药的主要成分，据报道，它对APL的CR率超过90%，以及我们新的合成维甲酸类化合物AM-80，它与细胞质维甲酸结合蛋白的亲和力很低。其升高是ATRA耐药的原因之一。在ATRA诱导缓解后复发的APL中，AM-80产生50%以上的CR，且通常对ATRA再次治疗具有抵抗力。As_2O_3似乎具有不同于ATRA的作用机制，因为它不仅能诱导NB-4细胞、APL来源的培养细胞以及患者的APL细胞发生凋亡，而且还能诱导分化。

The partners of this cooperative project, Prof.Z.Wang et al. at the Shanghai Second Medical School, reported for the first time in the world in 1998 that all-trans retinoic acid (ATRA), an active form of Vitamin A, produced 93% complete remission (CR) in acute promyelocytic leukemia (APL) as a differentiation therapy. After having a Joint Meeting of Japanese and Chinese Societies of Hematology in 1960, we started the ATRA therapy for chemotherapy-refractory APL, and confirmed its remarkable effectiveness in APL producing more than 80% of CR.Nowadays more than 60% of newly diagnosed APL patients are cured with ATRA and subsequent chemotherapy.This project mainly focused on the mechanism how ATRA works on APL from a molecular biological point on view. We have exchanged not only the knowledge and information on this point but also materials such as APL cells of patients from both countries and a monoclonal antibody, which had been produced in our laboratory, against the PML protein, the product of a plausible responsible gene on the leukemogenesis of APL.We have also exchanged newest information on a new promising therapy using As_2O_3 which is a main component of a Chinese traditional medicine against leukemia, and which reportedly produced more than 90% CR in APL by Chinese traditional medical doctors, and on our new synthetic retinoid, Am-80, with a low affinity to the cytoplasmic retinoic acid binding protein, an increase of which is one of the reasons of ATRA resistance. Am-80 produced more than 50% CR in APL which relapsed from ATRA-induced remission and is generally resistant to the re-treatment with ATRA.As_2O_3 seems to have a different mechanism of action from ATRA, since it not only induces differentiation but causes apoptosis in NB-4 cells, APL-derived cultured cells as well as APL cells from patients.