因为学生拜年提起了三氧化二砷的事, 我最近看了一下相关的新闻和文献, 发现了一个有趣的现象, 中美对于急性早幼粒白血病的特效药--

三氧化二砷的发现人有不同的认定. 国内认定张亭栋教授是三氧化二砷的发现人, 而美国认定三氧化二砷的发现人是陈竺教授.

张亭栋教授作为三氧化二砷的发现人得到陈竺教授等的支持 (见链接: http://www.hljwst.gov.cn/index/zsdw/2012120313175.htm). 陈竺教授和张亭栋教授一起申请美国的专利以及随后为张亭栋教授所做的广泛宣传体现了这种支持. 2001年, 张亭栋教授作为第一作者和陈竺教授合著综述: ‘Arsenic trioxide, a therapeutic agent for APL’ 发表在2001年 ‘Oncogene’上.

美国的认定从美国癌症基金会第七届圣捷尔吉癌症研究创新成就奖奖中可见一些端倪. 2006年, 我去美国, 顺便接触了一家著名医院的几名血液科临床医生(其白血病治疗在美国是前三名). 在关于三氧化二砷发现人的问题上, 他们均持有相同的观点, 陈竺是三氧化二砷的发现人. 当我表示异议时, 他们十分不解. 主任最后告诉或告诫我: "你难道没读过陈竺博士的文章吗"? 当时我觉得十分的困惑和自责. 虽然从1995年开始, 我陆续发表了15篇有关三氧化二砷的临床和机理研究文章(见附件张鹏等发表的相关文献.doc), 但确实退休后, 逐渐脱离了科研第一线, 很少阅读相关文献了.

最近托人找到了陈竺教授的几篇文章, 认真的拜读了一下, 才明白了其中的缘由.

首先拜读了陈竺教授1996年8月在Blood上发表的第一篇关于三氧化二砷的文章: In Vitro Studies on Cellular and Molecular Mechanisms of Arsenic Trioxide (As2O3) in the Treatment of Acute Promyelocytic Leukemia: As203 Induces NB4 Cell Apoptosis With Downregulation of Bcl-2 Expression and Modulation of PML-RARdPML Proteins.文章中关于三氧化二砷研究历史的叙述: Recently it has been shown that arsenic compounds including arsenic trioxide (As2O3)¹¹ and arsenic disulfide,¹² two components used in some traditional Chinese remedies, are very effective in APL treatment. For example, a report from the Northeast Region of China showed that As2O3 (10 mg/day, intravenous [IV] infusion for 28 to 60 days) induced clinical CR in 65.6% of APL patients. More interestingly, 28.2% (9 of 32) of patients had a survival of more than 10 years. At the Shanghai Institute of Hematology, a recent clinical trial with As2O3 treatment also showed that CR was achieved in 15 of 16 APL patients who relapsed after ATRA induced and chemotherapy-maintained CR (Z-X Shen, G-Q Chen, Z-Y Wang, Z Chen, in preparation). It is noteworthy that no significant bone marrow suppression was observed in most patients supervening As2O3 treatment. This situation differs significantly from that observed with conventional cytotoxic chemotherapy.

11 . Sun HD, Ma L, Hu XC, Zhang TD: Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integrat of Chinese and Western Medicine 12:170, 1992

12. Huang SL, Guo AX, Xiang Y, Wang XB, HJ Ling, L Fu: Clinical study on the treatment of APL mainly with composite Indigo Naturalis tablets. Chin J Hematol 16:26, 1995

十分奇怪, 文章中没有引用我们哈医大一院血液内科的工作. 难道陈竺教授没有出席1995年9月在大连的第八届全国白血病会议, 没有看到我们1996年2月在中华血液学杂志发表的文章: 张鹏，王树叶，胡龙虎等.三氧化二砷注射液治疗急性早幼粒细胞白血病72例.中华血液学杂志，1996，17（2）：58-60

接着拜读了陈竺教授2002年发表于自然综述(Nature  Review)的文章: How acute promyelocytic leukaemia revived arsenic 文章中关于三氧化二砷研究历史的叙述: A Chinese miracle              In the early 1970s, a group from Harbin Medical University in the northeastern region of China studied more than 1,000 cancer patients and found that intravenous infusions of Ailing-1 — a crude solution of As2O3 and trace amounts of mercury — could be used to treat patients with APL(9,10). Complete clinical remission was achieved in two-thirds of patients, with an impressive 30% survival rate after 10 years. From 1994, clinical trials with pure As2O3 were conducted in Shanghai Second Medical University, in collaboration with Harbin. They confirmed the efficacy of pure As2O3 in patients with APL who had undergone relapse after RA plus chemotherapy(11,12).

9. Sun, H. D. et al. Ai-ling 1 treated 32 cases of acute promyelocytic leukemia. Chin. J. Integrat. Trad. Chin. West. Med. 12, 170–171 (1992).

10. Zhang, P. et al. Treatment of 72 cases of acute promyelocytic leukemia with intravenous arsenic trioxide. Chin. J. Hematol. 17, 58–62 (1996).

显然, 第10 篇引文—我们的文章--被划入以癌灵1号治疗急性早幼粒白血病的范围. 这是一个错误. 我们是用As2O3进行的治疗急性早幼粒白血病的临床试验.

接着拜读了张亭栋教授作为第一作者和陈竺教授合著综述: Arsenic trioxide, a therapeutic agent for APL 发表在2001年 ‘Oncogene’上. 文章中关于三氧化二砷研究历史的叙述: Recently, a discovery on the therapeutic effect of As2O3 in acute promyelocytic leukemia (APL) has revived this ancient drug (Chen et al., 1996; Mervis, 1996; Look, 1998; Gallagher, 1998; Conrad, 1999; Warrell, 1999; Slack and Rusiniak, 2000; Wang and Chen, 2000; Chen et al., 2001). APL is a special subtype of acute myeloid leukemia (AML), characterized by the specific chromosomal translocation t(15;17) with resultant leukemogenic PML ± RARa fusion gene, and the clinical response to differentiation therapy using all-trans retinoic acid (ATRA) (Melnick and Licht, 2000). Over the past several years, As2O3 as an effective salvage treatment for relapsed and/or refractory APL patients has been confirmed worldwide. Recently, this drug was formally approved by the State Drug Administration (SDA) in China (1999) and the Food and Drug Administration (FDA) of the United States of America (Cohen et al., 2001). Encouraged by such a bedside discovery, mechanisms of action of As2O3 have been actively addressed by many groups. The potentials of As2O3 in the treatment of cancers other than APL are also under exploration. Here, we shall discuss the recent advances in the clinical practices and the mechanisms of action of As2O3 in APL. 这一叙述中依然没有引用我们哈医大一院血液内科的工作. 张亭栋教授首先引用了陈竺教授的第一篇关于三氧化二砷的文章证明: Recently, a discovery on the therapeutic effect of As2O3 in acute promyelocytic leukemia (APL) has revived this ancient drug.

接着拜读了陈竺教授的一篇综述: From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia. BLOOD, 16 JUNE 2011 VOLUME 117, NUMBER 24 文章中关于三氧化二砷研究历史的叙述: In the early 1970s, a group from Harbin Medical University in northeastern China tested Ailing-1 containing 1% ATO and a trace amount of mercury chloride in a variety of cancers by intravenous administration. In the 1990s, Sun et al(52) showed that Ailing-1 induced CR in 21 of 32 patients with APL with an impressive 10-year survival rate of 30%.  The efficacy of pure ATO in treating relapsed APL was then reported by Shanghai Institute of Hematology(SIH) in 1996-1999.(53,54) Shen et al (54) evaluated the therapeutic effect of ATO in the treatment of 15 patients with APL at relapse after ATRA-induced and chemotherapy-maintained CR. 文章中我们哈医大一院血液内科的工作消失了. 我认为不妥. 文章使用then 这个词明显想要误导读者.

显然, 美国医生并没有将癌灵1号等同于三氧化二砷. 如根据以上文章判断, 毫无疑问, 陈竺教授是三氧化二砷的第一发现人.