Differentiation therapy of acute promylocytic leukemia.

急性早幼粒细胞白血病的分化治疗。

• 批准号: 05044157
• 负责人: OHNO Ryuzo
• 金额: $ 2.88万
• 依托单位: Hamamatsu Univ.
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05044157/
• 关键词: all-trans retinoic acid; acute promyelocytic leukemia; Vitamin A; PML; As_2O_3; Am-80; apoptosis; retinoid; cytoplasmic retinoic acid binding protein; レチノイン酸; 分子生物学; PML遺伝子; RAR遺伝子

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.

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。

项目成果

大野 竜三: "図説臨床〔癌〕シリーズNo.17 白血病・リンパ腫 -新版- ATL,AIDS関連リンパ腫を含めて 第2章 骨髄性白血病〈治療〉(p32-40)" 杉村 隆 監修 末舛恵一,高山昭三,服部 信,正岡 徹 編集 メジカルビュー社, 274 (1994)

大野龙三：“图解临床[癌症]系列第17号白血病/淋巴瘤 - 新版 - 包括 ATL、艾滋病相关淋巴瘤第 2 章髓性白血病<治疗>（第 32-40 页）” 杉村隆 监督 末增敬一，高山 编辑Shozo、Makoto Hattori 和 Toru Masaoka，Medical View Publishing，274 (1994)

R.Ohno,et al.: "Treatment of adult T-cell leukemia/lymphoma with MST-16,a new oral antitumor drug and a derivative of bis(2,6-dioxopiperazine)" Cancer. 71. 2217-2221 (1993)

R.Ohno 等人：“用 MST-16 治疗成人 T 细胞白血病/淋巴瘤，MST-16 是一种新型口服抗肿瘤药物和双（2,6-二氧代哌嗪）衍生物”癌症。

Yoshida H, Naoe T, Ohno R.et al.: "Analysis of the joining sequences of the t (15 ; 17) translocation in human acute promyelocytic leukemia : Sequencenon-specific recombination between the PML and RARAgenes within identical short stretches." Genes Chrom C

Yoshida H、Naoe T、Ohno R.等人：“人类急性早幼粒细胞白血病中 t (15 ; 17) 易位连接序列的分析：相同短片段内 PML 和 RARA 基因之间的序列特异性重组。”

R.Ohno,et al.: "Multi-institutional study of all-trans retinoic acid as a differentiation therapy of acute promyelocytic leukemia." Leukemia. 7. 1722-1727 (1993)

R.Ohno 等人：“全反式视黄酸作为急性早幼粒细胞白血病分化疗法的多机构研究。”

Nagura,E.,Ohno,R.,et al.: "Nation-wide randomized comparative study of doxorubicin,vincristine and prednisolone combination therapy with and without L-aspara-ginase for adult acute lymphoblastic leukemia." Cancer Chemotherapy Pharmacology. 33. 359-365 (19

Nagura,E.、Ohno,R.等人：“多柔比星、长春新碱和泼尼松龙联合治疗（联合或不联合 L-天冬酰胺酶）治疗成人急性淋巴细胞白血病的全国随机比较研究”。