化毒为药：砒霜治疗白血病（英汉对照）

化毒为药：三氧化二砷对急性早幼粒白血病治疗作用的发现（英汉对照）

饶毅，黎润红，张大庆

摘要

在三氧化二砷（arsenic trioxide，ATO）被视为“对急性早幼粒白血病（APL）病人最为有效的单体”（Sanz et al., 2009; Tallman and Altman, 2009）的情况下，令人惊讶的是：最重要的发现者鲜为人知、其原始论文迄今未被一篇英文研究论文所引用。该发现产生于文化大革命时期，当时大多数中国科学家和医生处于困难时期。始于乡村中医针对性含糊的复方，张亭栋与同事于1970年代提出复方中单一的化学分子起作用、其最敏感对象为APL（张亭栋等，1973；张亭栋和荣福祥，1979）。张亭栋和同事二十多年的工作扫除了“能否”和“如何”有效使用ATO的困惑。此后中国和西方的其他研究者跟随张亭栋等的先驱工作。张亭栋小组回顾性分析自己的资料证明APL确实为ATO最敏感的对象（张亭栋和李元善，1984；孙鸿德等，1991）。张亭栋所在医院另一研究组将原本微量的氯化亚汞从配方中完全去除证明ATO单独可以治疗APL（张鹏等，1996）。1998年西方研究者发表重复和证明中国发现的论文导致ATO疗法被广泛接受（Soignet et al., 1998）。不过，ATO相关英文论文的西方或中国作者皆未引用张亭栋等1970年代的文章。本文集中介绍张亭栋等早期文献，但也提示进一步研究和验证中国报道ATO对其他肿瘤的作用，认为中国刊物发表的一些发现可能对病人有相当价值、其他国家的医生可能得益于有最大病人群落的中国医生之临床经验。

急性早幼粒白血病（APL）曾为急性白血病中发病最凶险和后果最致命之一，而现在是最能被治疗的白血病之一。虽然对APL的治疗还有可改进的余地，过去几十年来其治疗有很显著的改善，因为四类药物的应用：阿糖胞苷（cytarabine，arabinosyl cytosine, Ara-C) (Ellison et al., 1968)；蒽环类抗生素（anthracyclines）(Boiron et al., 1969; Bernard et al., 1973; Bernard, Weil and Jacquillant, 1974)；三氧化二砷（arsenic trioxide，As2O3，ATO) (Zhang et al., 1973; Departments, 1974; Rong and Zhang，1979; Zhang and Rong, 1979)；和全反型维甲酸（all-trans retinoic acid，ATRA）(Huanget al., 1987, 1988)。

四类药物中，阿糖胞苷、蒽环类抗生素（如柔红霉素，daunorubin）和维甲酸的发现广为人知，而ATO疗法的发现史鲜为人知：多数APL研究者引用1990年代的论文，晚于原创论文近二十年；有些作者不清楚ATO的最初发现者。这些错误令人遗憾，特别是考虑到欧洲白血病国际专家委员会已认为ATO是“APL疗法中最具生物学活性的单体”（Sanz et al., 2009）、也被认为是“APL病人最有活性的单体” （Tallman and Altman, 2009)，而ATO与ATRA合并用药可能“在不久的将来，在多数、如果不是全部病人中，替代传统疗法”（Tallman and Altman, 2009）。过去十余年来见证了ATO的普遍接受（Sanz and Lo-Coco, 2011）、愈来愈多的证明ATO在初发和复发APL病人中的作用（Powell et al., 2010; Estey, 2011）。

不知道和混淆早期工作的部分原因是早期文献发表于中国人也少读的中文期刊，但还有其他更复杂的因素。本文总结早期文献，从发现ATO治疗白血病到普遍接受ATO治疗APL。我们也提供早期中文文献的英文翻译，以便西方作者引用。

本文作者并非白血病的研究者，而是以科学史研究者的身份写此文。我们希望白血病的研究者和医生更为仔细地阅读原始文献。

1 ATO发现的文化环境和非典型历史

1960年代中期至1970年代中期，中国处于文革的动荡期，直接和间接影响了多于一代的中国人。有观点认为今天中国发生的部分乃文革的后果或对文革的反应，多数人认为文革是负面的，如果不是灾害性的。

文革很多极左政策，多数是有害的，但有些有混合、甚至正面的作用，这些正面作用有些源于政策制定者的意图、有些并非原意。一个政策是改善农村医疗条件，从城市医院派遣“流动医疗队”到乡村服务，医疗队走访多个村庄、医疗队成员轮换；另一政策是强调中国传统医药。这两项政策的交汇导致当时很多“发现”中医药有很强疗效的声称，其中多数在几年内被遗弃。但是，少数经受了时间的考验。ATO的发现是这种例子。

砷曾长期为中外使用。多种传统中药配方含砷，但通常含多种化学分子、针对的疾病不非常清晰。西方使用砷也不确定（Sears, 1988）。例如，1786年英国的Thomas Fowler 发明含砷化钾（KAsO2）的溶液，用于疟疾、间歇热、周期性头痛等（Sears, 1988）。1845年发现白血病后，Fowler氏液于1865年曾被用于治疗白血病，并于1931年再度用于白血病（Jolliffe, 1993），其后砷和放射作为治疗慢性髓细胞白血病（chronic myelocytic leukemia，CML）的主要疗法，直至1953年被马利兰（busulfan）化疗所替代（Sears, 1988; Jolliffe, 1993），不再是西方治疗白血病的常规药物。

1958年，中国哈尔滨医科大学的关继仁试用Fowler液治疗白血病，结论是砷剂无效（Guan, 1958）。

1950和1960年代，北京的周霭祥和上海的顾德謦使用含硫化砷的中药复方治疗白血病（Gu, 1964）。1972年，一个标明“内部资料”的刊物“辽宁抗癌战讯”发表朝阳人民医院儿科的文章，报道用砷剂和化疗合并治疗16例儿童急性粒细胞白血病。这一治疗未分开砷剂和其他化疗，不清楚砷剂是否有超出其他化疗已有的效果，也不知道有多大效果：未报道16例病人的成功率、仅分析了一例的血象。

1974年中医研究院血液组总结了全国当时已经试过的、基于中医药的白血病治疗途径和药物，它列了硫化砷（As2S3）和蟾酥（以及其他，包括完全西方发明的药物）（Hematology Group, 1974）。它将关继仁（1964）和朝阳人民医院（1972）作为支持As2S3疗效的两篇文献。需要指出，顾德謦和周霭祥并未将他们的复方化解为单方，即使到今天（如，Zhou，1998；Hu et al., 2011）。因为含As2S3的中药制备过程并无使As2S3氧化为ATO的高温，在这些砷剂中As2S3与ATO的关系不明。1974年的综述没有结论建议用哪种中药治疗白血病，该文所讨论治疗白血病的蟾酥和多种其他中药其后并未成为任何亚型白血病的标准疗法。

总之，至1974年，并无定论用什么中药治疗白血病、已试过的中药的有效性也未确切公认。

1970年代初，哈尔滨医科大学附属第一医院药剂科的韩太云参加巡回医疗队，得知乡村中医用含砷、汞和蟾毒等的复方治疗淋巴结核和多种癌症。1973年3月，韩太云将这三者做成注射液，他按年月命名为“713”溶液、亦称“癌灵”。肌肉注射“713”对有些癌症病人有效，一时风靡当地，但又因其毒性很快消停。“713”针对的疾病并不清晰，其有效成分也未确定。

张亭栋与韩太云同在一个医院。张亭栋出生于1932年，于1950年代早期学习西医后毕业于哈尔滨医科大学，1960年代曾进修中医，长期工作于哈尔滨医科大学附属第一医院中医科。他曾被黑龙江省卫生局派去检查乡村中医所言是否属实，以后张亭栋与韩太云合作。

2 ATO治疗APL的原始发现: 1973至1979

1972年后，张亭栋与同事将研究集中于白血病。他们也思考了“713”的成分，提出砷是唯一的治疗性化学分子，而汞与蟾酥汞无治疗白血病的作用，汞导致肾毒性、蟾酥导致高血压等副作用。从此，他们用的“癌灵1号”主要含ATO、仅微量汞（ATO与氯化亚汞的重量比为100：1），而全无蟾酥。

1973年，张亭栋与韩太云的第一篇文章发表于当地的中文刊物。张亭栋、张鹏飞、王守仁、韩太云报道“癌灵”治疗6例慢性粒细胞白血病（Zhang et al., 1973）。他们明确陈述所用溶液含ATO和微量氯化亚汞，所有6位病人都在治疗后有改善，他们提到还在治疗急性白血病，但该文中未发表其结果。

1974年，哈尔滨医科大学第一附属医院中医科和检验科为集体作者在该校的校报发表文章（Departments, 1974），总结1973年1月至1974年4月治疗的17例白血病人。在观察不同类型白血病后，他们报道癌灵1号可以治疗多种白血病，有些可以达到完全缓解（complete remission，CR）。1976年，他们以集体作者还发表了5例急性白血病的治疗，皆CR。

1979年，荣福祥和张亭栋报道两例急性粒细胞白血病，一例CR已4年、一例3年（Rong and Zhang, 1979）。

1979年，张亭栋和荣福祥发表当年的第二篇文章，总结他们治疗55例急性白血病（Zhang and Rong, 1979）。其中，23例从1973年至1974年仅用癌灵1号，20例从1975年至1976年用癌灵1号加西医化疗及其他中药，12例从1977年至1978年用癌灵1号加中药和化疗。对每个病人，他们显示了白血病的亚型和临床观察。所有55例都有一定程度的改善，总缓解率为70%，而12例为CR。他们用的剂量副作用较小。他们以相当于成人剂量十倍的剂量注射到家兔，病理解剖后没有见心、肝、脾、肾的毒性。

1973年文章报道了他们先驱的发现，1979年的第二篇文章代表他们对疗效的理解（Zhang and Rong, 1979）。张等早期工作有三个重要问题：1）他们是否证明治疗作用来源于癌灵一号，而不是其他中药或化疗西药？2) 他们是否意识到癌灵1号的作用来源于ATO而不是溶液中的汞？3）他们是否知道ATO对APL的作用？

以上三个问题的答案都可在Zhang and Rong (1979) 一文看到：1）三例患者（一例成人、两例儿童）只用了癌灵1号，未用其他任何西药和中药，疗效显著。论文发表时，儿童存活4年多、成人逾9给月。当使用其他中药时，他们指出不是治疗白血病，而是支持患者健康状态以便接受治疗；2）他们文章第11页提出癌灵1号的有效成分是ATO；3）他们在文章的第10和11页反复指出ATO最敏感的白血病是法国-美国-英国FAB分型的M3型（另一名称为APL ）。

我们可以看到，至1979年，张亭栋和同事的理解与现在相同：ATO可以治疗白血病，特别是M3型（亦称APL）的白血病。

3 张亭栋研究组1980至1990年代的进一步工作

1981年，以集体作者（但标明张亭栋为指导，含8位其他作者）的文章报道，癌灵1号使73位急性粒细胞白血病人中24%的CR、总缓解率86%（Department, 1981）。1982年，张亭栋和李元善在全国会议上报道癌灵1号治疗后CR的22例、以及治疗98例非淋巴细胞白血病，张在1982和1983年总结其工作（Zhang, 1982, 1983)。

1984年，张亭栋和李元善总结他们自1971年以来治疗的81例患者（Zhang and Li，1984）。在CR的22例中，他们指出7例为M2型、15例为M3型。他们再次认为“以M3型效果尤为显著”。张亭栋另发文章有关癌灵1号对非淋巴细胞型白血病的作用（Zhang，1985）。

1991年，孙鸿德、马玲、胡晓晨、张亭栋、荣福祥、王钦华、李金梅、冯秀芹 (Sun et al., 1991) 继续1984年张亭栋和李元善的工作。他们报道癌灵1号从1974年至1985年已用于治疗32例APL，其中19例CR、16例缓解超过5年，通过分析更多病例验证了ATO治疗APL的高效。

1992年，孙鸿德、马玲、胡晓晨、张亭栋（Sun et al., 1992）以短篇“经验交流”综述了与他们1991年文章完全相同的实质内容。奇怪的是，多数英文文章都引用1992年这篇文章作为发现ATO治疗APL，虽然这两篇文章皆中文。

因为张亭栋从1973至1992年的文章所报道的治疗都含微量氯化亚汞，虽然远低于ATO（重量比1:100），严格地说，他们未证明氯化亚汞毫无益处，虽然他们在1973年的文章中就说过癌灵1号的有效成分是ATO。

1995和1996年，张亭栋同一医院的张鹏、王树叶、胡龙虎、施福东、邱凤琴、洪珞珈、韩雪英、杨惠芬、宋颖昭、刘艳平、周晋、金镇敬等发表两篇论文，证明没有汞的情况下，仅有ATO也完全有疗效（Zhanget al., 1995, 1996）。1995文章为摘要，没有明确所用的“713”注射液不含汞，不过后来张鹏说明他们只用了ATO（Zhang，2013）。1996年文章明确只有ATO、无氯化亚汞。他们从1992年至1995年治疗了130位患者，其中72例一次或多次治疗。他们治疗初发病人的CR可达73%，在复发再治病人的CR可达52%（Zhanget al., 1996）。

在发掘ATO研究的过程中，我们没有看到迹象证明传统中医理论对疾病的分型对发现ATO的靶疾病有用。在此，我们将传统中国医药分成中医理论（CMT）和中药。CMT对发现ATO治疗白血病重要吗？张亭栋等讨论了依据CMT对白血病分五类，但ATO对这些类型作用无差别（Rong and Zhang, 1979; Zhang and Rong, 1979; Departments, 1984）。而西医对白血病的分型有助于发现ATO的靶疾病。当他们完全放弃CMT对白血病的分型时，ATO对靶疾病的作用更为显著。有趣的是，他们1973年第一篇文章并未用CMT，而后来的文章提到。缺乏支持CMT用处的证据并不能证明CMT无用，但迄今不明确CMT是否对于传统中药的研究是否重要。

4 中国对APL治疗的贡献

阿糖胞苷和蒽类抗生素（包括柔红霉素）等因为西方的研究成为APL的一线药物（Ellisonet al., 1968; Boiron et al., 1969; Bernard et al., 1973）。此后，中国因为ATO和ATRA的发现而有显著改善APL的治疗。本文将中国的发现放在当时的历史框架中。

1973年，中国的张亭栋和同事报道ATO对白血病的治疗（Zhang et al., 1973）。1979年张亭栋和荣福祥提出APL对ATO特别敏感（Zhang and Rong，1979）。

1977年，美国癌症研究所的Collins等成功地从APL病人来源的细胞建立了细胞系（HL-60）（Collins, Gallo and Gallagher，1977。1978年，Collins等用此细胞系筛选药物，找可诱导HL-60细胞分化成熟为正常细胞的化合物。1980年，Brietman, Selonick and Collins 发现全反型维甲酸（ATRA）和13顺型维甲酸可以诱导HL-60分化为成熟的细胞，相关的化合物如维生素A作用低一千倍。他们提出“这一化合物可以提供治疗急性髓细胞白血病的新治疗工具”。

1981年，Breitman、Collins和Keene从白血病患者血中获得白细胞，检测它们对药物的敏感性，发现ATRA能够诱导分化的细胞皆来自两位APL患者。1982年，Olsson和Brietman发现维甲酸也能诱导U-937淋巴瘤细胞分化。1983年，日本的Honma等报道多种化合物可以诱导不同白血病人的细胞分化，发现ATRA可以诱导APL患者白细胞的分化。美国的Koeffler (1983) 总结了体外结果，包括用维甲酸和其他化合物诱导细胞分化，认为ATRA和13顺维甲酸对APL白细胞有同等的分化诱导作用。

美国和欧洲的四个研究组分别报道了13顺维甲酸成功地治疗APL个例：美国明尼苏达的Flynn等(1983)；瑞典Lund的Nilsson (1984)；荷兰的Daenen等(1986) ；以及美国西佛吉尼亚的Fontana, Roger and Durham (1986)。

1985年，上海第二医学院的王振义在当地能获得ATRA，但不能获得13顺维甲酸，他用ATRA成功地治疗了一例5岁APL女孩。1987年，他的研究组在《中华医学杂志》发表英文论文，报道单用ATRA、或ATRA合并其他化疗治6例APL患者（Huanget al., 1987）。1988年，王振义研究组在国际的《血液》杂志发表他们用ATRA治疗24例APL（Huang et al., 1988）。该文引用了1980年Breitman、Selonick,、Collins的文章，1981年Brietman,、Collins、Keene 的文章，以及1983年Koeffler报道ATRA和13顺维甲酸诱导白细胞分化的文章，也引用了1983年Flynn et al.、1984年Nilsson、1986年Daenen et al.及Fontana et al.等报道13顺维甲酸治疗APL的多篇文章。

Huanget al.在1988和1987年的两篇都是英文论文，但1988年的文章在美国发表、1987年的文章在中国发表，前者获国际关注。与法国医生的直接交流也有助于国际关注。王振义研究组ATRA的发现很快被重复。1989年，法国的Chomienne等将ATRA和13顺维甲酸分别给两例APL患者，比较两个药物的疗效，感觉ATRA更有效。1990年，同一法国研究组在体外研究了来自于22例APL患者的白细胞，认为ATRA的作用是13顺维甲酸的十倍（Castaigne et al., 1990）。ATRA的作用也被中国其他医生验证（如，Chen ZX et al., 1991）。1991年，美国的Warrell等验证了中国王振义组和法国Degos组的疗效，成功地治疗了11例APL中的9例。自此，ATRA治疗APL广为人知。1997年，Tallman等报道用346例APL比较ATRA和此前标准化疗的柔红霉素和阿糖胞苷，发现如果ATRA在诱导和维持期都用时疗效高于化疗。

1992年，段秀绵、辛晓敏、王凤芹、冯秀芹、徐敬肃、宋晓时、张月桂报道ATO体外对白细胞的作用。1995年，大连的黄世林、郭爱霞、向阳、王晓波、林慧娴、富丽报道复方青黛片在65位APL患者中获98%的CR，他们用药成分中含硫化砷。

1995年和1996年2月，哈尔滨的张鹏、王树叶、胡龙虎、施福东、邱凤芹、洪珞珈、韩雪英、杨惠芬、宋颖昭、刘艳平、周晋、金镇敬报道从1992年至1995年在130位APL中单用ATO获得73%的CR。ATO与ATRA之间无交叉耐受（Zhang et al., 1995, 1996）。

1996年8月，上海第二医学院血液研究所的陈国强等19位作者（包括中间作者张亭栋、最后作者陈赛娟、王振义、陈竺）报道用体外培养的白血病细胞在分子水平研究ATO的治疗机理（Chen et al., 1996）。

1997年, 徐敬肃、段秀绵、徐莹、辛晓敏、宋晓红、张亭栋报道一例三度发病的APL患者，每次用癌灵1号治疗后存活了二十多年（Xu et al., 1997）。

1997年，上海血液所的陈国强等报道ATO体外作用于白血病细胞的良效关系。1997年，上海上海血液所的的沈等报道15例APL患者的治疗，其中10例单用ATO，CR达90%。

1998年，美国Sloan-Kettering癌症研究中心和康奈尔医学院的Soignet 等在《新英格兰医学杂志》报道他们用ATO治疗12例复发的APL患者，11例CR（Soignet et al.，1998）。

Soignet等的1998年论文很有利于国际接受ATO作为APL的治疗方式，这是中国医生此前二十多年在国内发表的很多文章未能做到的。

5 缺乏认可

现在，国际和国内都很接受和使用ATO，救活了中外患者。但是，发现者基本在学术和医疗社群默默无闻，尽管2001年曾有《纽约时报》的报道（Rosenthal, 2001）。更为鲜明对照的是，虽然ATRA治疗APL导致王振义获得多个国内外荣誉，张亭栋或他的哈尔滨同事没有因为ATO治疗APL而获一个全国性或国际性奖励。而我们知道，ATO的发现早ATRA十余年，且为欧洲白血病专家委员会认为是“APL最具生物学活性的化合物”（Sanz et al., 2009）。

缺乏认可并非因为争议。张亭栋研究组的孙鸿德曾提出专利争议，但提出时间较晚，而且法院判案支持张亭栋。张鹏坚持他第一证明ATO无需汞可以单独治疗APL。确实，1979年张亭栋和荣福祥曾提出ATO单独有作用，但他们没有显示单独用ATO的资料。孙鸿德和张鹏有重要贡献，但很清楚张亭栋的作用毫无疑问最为关键，他从1970年代初到1990年代初坚持不懈的工作，改观了人们对砷之用处和效果的想法：以前砷无确切的用法、疗效不定，他的工作后砷的使用实际可行、且疗效显著。

1998年，陈国强、陈赛娟、王振义、陈竺在中文杂志表示：自1970年代初，哈尔滨医科大学通过临床实践发现三氧化二砷可以有效地治疗APL，近两年来，我们与哈医大合作，用三氧化二砷溶液治疗对全反维甲酸和化疗耐药的APL患者（Chen et al., 1998）。这类陈述肯定了哈尔滨工作的优先，不过这篇综述文章中没有出现张亭栋的名字、也未引用其1970年代的文献。

几乎没有英文论文意识到张亭栋在1973至1979年已发表过论文。英文论文，即使是中国学者的英文论文，也仅引1992年孙鸿德等（Sun et al.，1992)、有时引用1996年张鹏等的论文（Zhang et al.，1996），视它们为ATO治疗白血病的最早论文。例如，1998年Soignet等文章重复张亭栋1970年代论文、并对国际接受ATO起了很大作用，但它称“中国最近报道”ATO治疗APL导致CR，引用的是1992年孙鸿德（Sun et al.，1992)、1996年张鹏等（Zhanget al.，1996)、1997年上海血液所的沈等（Shen et al.，1997)。从1998年Soignet等论文不可能知道张亭栋在1970年代就有原创的发现，因为文章的基调和引用让读者认为中国的发现是在1990年代。

美国的《科学》杂志在1996年一篇新闻报道曾提到张亭栋（Mervis, 1996），但却称张亭栋于1992年发表论文。

张亭栋本人很少发表英文论文。2001年，他与陈国强作为共同第一作者、王振义和陈赛娟作为中间作者、陈竺作为通讯作者在国际杂志《癌基因》发表综述（Zhanget al., 2001）。在引言部分，他们说“最近”研究ATO治疗APL，引用的是1996年上海血液所等陈国强等（Chen et al.，1996)。第二页，他们说ATO的研究始于1971年，但未引用任何文献；也说他们治疗了包括慢性粒细胞白血病、淋巴瘤、食管癌以及特别是APL等多种癌症、上千患者，但还是没引文献。如此，张亭栋看起来作为第一作者的英文论文也没引用他自己早年的文献，有效地埋葬了1970年代的先驱工作。

2002年，朱军、陈竺、Lallemand-Breitenbach和de The在《自然综述癌症》发表综述文章。在描绘APL治疗里程碑的图中有张亭栋在1970年的工作，但文字部分引用还是1992年孙鸿德等（Sun et al.，1992)，在参考文献中称1992年孙鸿德等的文章为“第一篇三氧化二砷治疗APL的报道”。

1992年孙鸿德等和1996年张鹏等皆为中文论文，却都未引用1970年代的文献。所以，如果有国际学者希望通过有人帮助他们翻译1992和1996的文章，他们也不可能由此知道1970年代的原始文章。

2008年，王振义和陈竺在《血液》发表APL治疗进展的综述，其对ATO引用的第一篇是2002年朱军等（Zhuet al.，2002)，后面还引了1992年孙鸿德等、1996年张鹏等，以及上海血液所三篇文章（1996年陈国强等、1997年沈等、1999年牛等)。

2011年，陈赛娟和陈竺等五位作者发表ATO治疗APL的综述（Chen et al.，2011），称“1970年代早期，中国东北哈尔滨医科大学一个小组检测了含1%ATO和微量氯化亚汞的癌灵1号在静脉注射后对多种癌症的作用”，但未说明研究者、也未引用1970年代的文献。它1992年孙鸿德等作为“癌灵1号在32位患者中21位CR，并有30%的令人印象深刻的十年存活率”，然后说“单独用ATO治疗复发的APL是上海血液研究所自1996年至1999年报道的”，引用上海的文章是1997年沈等和1999年牛等, 忽略哈尔滨张鹏等1995和1996年的两篇文章，其中1996年张鹏等说明了只用ATO、无氯化亚汞。按照张鹏于2013年的博客文章，张鹏等的结果于1995年在全国会议上宣读，陈竺等出席会议者应该知道（Zhang, 2013）。但按2011年陈赛娟和陈竺等在国际刊物的综述，首先报道单独用ATO治疗APL不是1996年的张鹏等、而是上海血液所在1997和1999的文章。

2011年香港一篇文章，跟踪ATO治疗APL十年的疗效，但它只引用美国作者2001年的文章（Auet al.，2011），连内地作者1990年代的文章也不引。

这样，本来应该可以读中文的作者无一在发表英文论文时引用了1970年代的文章。在当今英文作者连法文和德文也不读的情况下，毫不奇怪他们不知道中文的原始文献。张亭栋的贡献、他发现的准确时间因此而不为国际学术和医疗界所知。

6 注意中文发表的工作之意义

过去，一般倾向于忽视中国的临床研究，语言只是部分理由。有大量病人的中国，其医生常常有多于西方医生的临床经验。有些中国医生，即使是少部分中国医生，可能对治疗有洞见，但只发表在中国刊物。

以ATO为例，包括张亭栋在内的中国医生报道了ATO治疗多种癌症，从肝癌、胃癌、结肠癌到淋巴瘤（Li et al., 1988; Liu et al., 2005; Guo et al., 2006）。这些似乎值得验证。

间接推断中药成分的严格科学研究还可能有更多发现。例如，一些医院自己试用的药物、和一些中药企业在缺严格测试就猛力推进市场的药物。而可能在严格检验和研究后，会更为有效和有针对性，而更获得国际接受，最终帮助更多病人，挽救更多生命。

致谢

作者之一（YR）感谢中医研究院李连达告知两篇文章（Guan 1958, and Chaoyang People’s Hospital, 1972），以及周霭祥和顾德馨的工作。

（本文英文和中文分别发表于2013年《中国科学生命科学》的英文版和中文版）

Rao Y, Li RH, Zhang DQ (2013). A drug from poison: how the therapeutic effect of arsenic trioxide (ATO) on acute promyelocytic leukemia (APL) was discovered. Science China Life Sciences 56:495-502.

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Notes: Articles published in Chinese are listed in their original titles followed by a translation. Because several Chinese journals did not have regular volume numbers in the 1970s and 1980s, the year of publication and the issue within that year are listed. PDF files of the major Chinese papers can be accessed at the blog of YR: http://blog.sciencenet.cn/blog-2237-658474.html.

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英文发表于2013年《中国科学生命科学》英文版

Rao Y, Li RH, Zhang DQ (2013). A drug from poison: how the therapeutic effect of arsenic trioxide (ATO) on acute promyelocytic leukemia (APL) was discovered. Science China Life Sciences 56:495-502.

A drug from poison: how the therapeutic effect of arsenic trioxide (ATO) on acute promyelocytic leukemia (APL) was discovered

Yi Rao1, *, Runhong Li2and Daqing Zhang2

1Peking-Tsinghua Center for Life Sciences at Peking University School of Life Sciences and 2Peking University Health Sciences Center

Beijing 100871, China

*To whom correspondence should be addressed.

Abstract:

It is surprising that, while arsenic trioxide (ATO) is now considered as “the single most active agent in patients with (APL)” (acute promyelocytic leukemia) (Sanz et al., 2009; Tallman and Altman, 2009), the most important discoverer remains obscure and his original papers have not been cited by a single English paper. The discovery was made during the Cultural Revolution when most Chinese scientists and doctors struggled to survive. Beginning with recipes from a countryside practitioner that were vague in applicable diseases, Tingdong Zhang and colleagues proposed in the 1970s that a single chemical in the recipe is most effective and that its target is APL. More than 20 years of work by Zhang and colleagues eliminated the confusions about whether and how ATO can be used effectively. Other researchers, first in China and then in the West, followed his lead.Retrospective analysis of data from his own group (Zhang and Li, 1984; Sun et al., 1991) proved that APL was indeed the most sensitive target. Removal of a trace amount of mercury chloride from the recipe by another group in his hospital (Zhang et al., 1996) proved that only ATO was required. Publication of Western replication in 1998 made the therapy widely accepted (Soignet et al., 1998), though neither Western, nor Chinese, authors of English papers on ATO cited Zhang’s papers in the 1970s. This article focuses on the early papers of Zhang, but also suggests it worth further work to validate Chinese reports of ATO treatment of other cancers, and infers that some findings published in Chinese journals are of considerable value to patients and that doctors from other countries can benefit from the clinical experience of Chinese doctors with the largest population of patients.

Acute promyelocytic leukemia (APL) had been one of the most aggressive and fatal forms of acute leukemia, but is now one of the most treatable form of leukemia. While there are still room for improvement in treating APL, significant progress have been made in the last few decades by the applications of cytarabine (arabinosyl cytosine,Ara-C) (Ellison et al., 1968), anthracyclines (Boiron et al., 1969; Bernard et al., 1973; Bernard, Weil and Jacquillant, 1974), arsenic trioxide(As2O3, ATO) (Zhang et al., 1973; Departments, 1974; Rong and Zhang, 1979; Zhang and Rong, 1979) and all-trans retinoic acid (ATRA)(Huanget al., 1987, 1988).

The discoveries of cytarabine, anthracyclines and ATRA are well known, whereas the history of the discovery of ATO therapy remains unknown. Most APL researchers cited papers published in the 1990s, which were 20 years later than the original papers. Some authors also seem to be confused about the original discoverer of ATO. These mistakes are regrettable when ATO is now considered to be “the most biologically active single drug in APL” by a panel of International Leukemia Experts for the European LeukemiaNet (Sanz et al., 2009) or “the single most active agent in patients with APL” (Tallman and Altman, 2009) and that the combination of ATO and ATRA holds the promise to “replace conventional approaches for most, if not all, patients in the very near future” (Tallman and Altman, 2009). The past decade has witnessed the general acceptance of ATO (Sanz and Lo-Coco, 2011) and accumulating proof of more ATO applications from relapsed APL to newly diagnosed APL (Powell et al., 2010; Estey, 2011).

Ignorance of, and confusions about, the early work result in part from the fact that the original papers were published in the Chinese language and in journals that are obscure even to most Chinese readers, although there are other factors of a more complex nature. This article summarizes the early papers from the discovery of ATO treatment of leukemia to the general acceptance of the use of ATO in treating APL. We also provide a list of the early papers in English for Western authors to use in citations.

We note that the authors of the present article have not worked on leukemia and write this article in our roles as researchers in the history of science. We hope that those working on leukemia can go into more details of the original work

1 Cultural Milieu and Historical Peculiarities of the Discovery

In the 1960s and early 1970s, China was in a political turmoil known as the Great Proletarian Cultural Revolution. Although its origins lie in the political intentions of Mao Zedong, the supreme leader of China at the time, the Cultural Revolution has affected more than one generation of Chinese people directly and indirectly. Some would view what is happening in China now in part as a consequence of, or a reaction to, the Cultural Revolution, with most viewing the Cultural Revolution as negative, if not disastrous.

Of the many leftist policies during the Cultural Revolution, most were harmful, but some had mixed or even positive effects intended or unintended by the policy maker(s). One policy directly related to Mao was to improve the medical conditions of rural China by sending doctors from urban hospitals to the countryside in “Circulating Medical Teams”. Doctors in such teams will go to multiple villages and members of the team will rotate. Another policy was to emphasize the importance of Chinese medicine and drugs. The interception of these two led to many claims of findings of great effects of some Chinese medicines or treatment, most of which were abandoned within a few years. However, a few have withstood the test of time. The discovery of ATO was one such example.

Arsenic has been used for a long time, both in China and in the West. Several traditional Chinese medical recipes contain arsenic, but they were combinations of multiple chemicals with unclear targets. Western uses of arsenic were also ill-defined (Sears, 1988). For example, Thomas Fowler of Britain invented a solution containing potassium arsenite (KAsO2) in 1786, and used it for agues, remittent fevers and periodic headaches (Sears, 1988). After leukemia was discovered in 1845, Fowler’s solution was used in treating leukemia in 1865, and again in 1931 (Jolliffe, 1993). Arsenic and irradiation were the main forms of treatment for chronic myelocytic leukemia (CML) until 1953, when they were replaced by chemotherary with busulfan (Sears, 1988; Jolliffe, 1993). Arsenic treatment of leukemia was no longer a standard drug for leukemia in the West from then on. In China, Jiren Guang, a doctor in Harbin Medical University, tried to use Fowler’s solution to treat leukemia in 1958 and came to the conclusion that it was not effective (Guan, 1958). In the 1950s and 1960s, Aixiang Zhou in Beijing and Deqing Gu in Shanghai used combinations that included arsenic sulfate to treat leukemia (Gu, 1964). In 1972, a report appeared in Anti-Cancer Battle News of Liaoning Province, a publication explicitly labeled as “internally circulated materials” under the authorship of Chaoyang People’s Hospital Department of Pediatrics. It reported the treatment of 16 cases of acute granulocytic leukemia children by a combination of arsenic and chemotherapy. Because this treatment did not separate arsenic from the chemotherapy available then, it was unclear whether arsenic was helpful as an addition to chemotherapy, nor was it known how effective the combination was: success rate among the 16 patient was not reported and blood analysis was shown for only one patient. A 1974 review by the Chinese Academy of Traditional Medicine summarized different approaches and medicines for leukemia treatment by traditional Chinese medicine listed As2S3and toad venom (and others, including pure chemicals of Western invention) (Hematology Group, 1974). It cited Guan (1964) and Chaoyang (1972) as supporting the use of As2S3. It should be noted that neither Gu nor Zhou has reduced their recipes to a single component, even today (e.g., Zhou, 1998; Hu et al., 2011). Because the preparation and processing of the Chinese medicine containing As2S3did not involve the high temperature required for the conversion of arsenic sulfate into ATO, the relation of arsenic sulfate with ATO in such recipes is unclear. The 1974 review did not provide a conclusive recommendation on the type of Chinese medicine for the treatment of leukemia. Toad venom and quite a number of other medicines discussed in that review have not become a standard therapy for any type of leukemia. In summary, by 1974, it was unclear which of the traditional Chinese drugs can be used to treat leukemia and the effectiveness of those tested by then were uncertain.

In the early 1970s, Taiyun Han, a pharmacist of the First Affiliated Hospital of Harbin Medical University, was a member of a circulating medical team. He learned that a countryside practitioner of traditional Chinese medicine used a combination of arsenic, mercury and toad venom to treat lymphatic tuberculosis and cancers. In March 1971, Han made a solution that contained these three components, which he called “713” (after the year and month of his preparation) or “Ailin (literally meaning cancer effective)”. Intramuscular injection showed effects in some cancer patients. The “713” solution was hotly sought after locally for a while but faded soon from the public because of its toxicity. The target diseases of 713 were undefined, nor were the active chemical in 713.

Tingdong Zhang was a doctor in the same hospital as Han. Zhang was born in 1932 and graduated in the 1950s from Harbin Medical University, after studying the regular (Western) medicine. He took classes of traditional Chinese medicine in the 1960s. He worked in the Department of Traditional Chinese Medicine of the First Affiliated Hospital of Harbin Medical University. He was initially asked by the Health Bureau of Heilongjiang province to examine the validity of the claims of the countryside practitioner and later collaborated with Han.

2 Original Discovery of the Effective Treatment of APL by ATO: 1973 to 1979

After 1972, Zhang and colleagues focused their research on leukemia. They also analyzed the components of “713” and suggested that arsenic was solely responsible for the therapeutic effect, whereas mercury caused kidney toxicity and toad venom caused hypertension. Neither of the latter two was therapeutically useful for leukemia. From then on, their recipe of Ailin I was mainly ATO with a trace amount of mercury (at a ratio of 100 to 1 by weight), without toad venom.

The first paper by Zhang and Han was published in 1973 in a local Chinese journal. Tingdong Zhang, Pengfei Zhang, Shouren Wang and Taiyun Han reported that they had used “Ailin solution” (also known as “Ailin I”) to treat six cases of chronic granulocytic leukemia (Zhang et al., 1973). They explicitly stated that the components of the solution were ATO and a trace amount of mercury chloride. All six patients improved after the treatment. They also mentioned that acute leukemia patients were being treated, but with no results in that paper.

In 1974, under the collective institutional authorship of the Department of Traditional Chinese Medicine and the Department of Laboratory Medicine of Harbin Medical University, they published a report in the university journal (Departments, 1974), summarizing the treatment of 17 cases of leukemia patients from January 1973 to April 1974. After going through different types of leukemia, they reported that Ailin I was effective in treating multiple types of leukemia, leading to complete remission (CR) in acute leukemia patients. In 1976, they used an institutional authorship to publish a report on five cases of acute leukemia in which they had achieved CR.

In 1979, Fuxiang Rong and Zhang published two cases of acute granulocytic leukemia, one with CR for 4 and half years and the other for 3 years (Rong and Zhang, 1979).

A second paper by Zhang and Rong in 1979 summarized their treatment results from 55 cases of acute leukemia (Zhang and Rong, 1979). 23 leukemia patients were treated with Ailin I alone (from 1973 to 1974), 20 were treated with Ailin I in combination with Western chemotherapy and other Chinese medicines from 1975 to 1976, and 12 treated with Ailin I plus other Chinese medicines and chemotherapy from 1977 to 1978. For each patient, they presented leukemia subtypes and clinical observations. All 55 cases improved to some extent, with a remission rate of 70% and with CR in 12 cases. Side effects were small with the doses they used. They then applied 10 times the equivalent of what they used for adult human patients to 12 rabbits. No toxicity was observed in the heart, the liver, the spleen or the kidney of the rabbits.

While the 1973 paper reported their pioneering findings, the second 1979 paper represented their understanding of the therapeutic effect(Zhang and Rong, 1979). There are three important questions about early work of Zhang and colleagues: 1) had they shown that the therapeutic effect came from Ailin I, but not from other Western chemicals or Chinese medicines? 2) had they realized that the effect of Ailin I came from ATO but not from mercury in the solution? 3）had they known the effect of ATO on APL?

Answers for all three questions can be found in Zhang and Rong (1979) which explicitly stated：1）that significant improvement was observed in three patients (one adult and two children) used only Ailin I, but no other Western or Chinese drugs. At the time of publication, the children had survived for more than 4 years and the adult more than 9 months. When using other Chinese medicines, Zhang and Rong pointed out that those were not used for treatment of leukemia, but for supporting the general health of the patients so that they could tolerate more treatments; 2）that the effective component of Ailin I was ATO (on page 11 of their paper); 3）that acute granulocytic leukemia (M3 type of the French-American British FAB classification, also known as APL) was the most sensitive to the treatment, which was a conclusion reiterated on pages 10 and 11 of their paper.

We can see that, by 1979, Zhang and his collaborators had clearly reached our current understanding: that ATO could treat leukemia, especially that of the M3 subtype or APL.

3 Further Studies by the Zhang Group from the 1980s to the 1990s

In 1981, a paperunder an institutional authorship with a footnote indicating Zhang as the supervisor (with 8 other authors) reported 73 cases of acute granulocytic leukemia patients, with a CR of 24% and remission rate of 86% after Ailin I treatment (Department, 1981). In 1982, Zhang and Li presented a report to a national meeting on 22 cases of CR by Ailin I and on 98 cases of non-lymphatic leukemia. In 1982 and 1983, Zhang published reviews of his work (Zhang, 1982, 1983).

Zhang and Li (1984) published a summary of 81 cases which they had treated since 1971. Among the 22 cases of CR, they pointed out that 7 were of the M2 type and 15 were of the M3 type. They again stated that the effect on M3 type were particularly obvious. Zhang (1985) published another paper on the effect of Ailin I on non-lymphatic acute leukemia.

In 1991, Hongde Sun, Lin Ma, Xiaocheng Hu, Tingdong Zhang, Fuxiang Rong, Qinghua Wang, Jinmei Li and Xiuqing Hong (Sun et al., 1991) continued the work of Zhang and Li(1984). They reported that Ailin I had been used to treat 32 APL cases from 1974 to 1985, with CR in 19 cases and that 16 cases had survived for more than 5 years. This confirms the high success rate for ATO treatment of APL.

In 1992, Hongde Sun, Ling Ma, Xiaocheng Hu and Tingdong Zhang published a short “Sharing Experience” paper (Sun et al., 1992), reviewing materials identical to the 1991 paper. Oddly, most English papers cite this 1992 paper for the discovery of ATO treatment of APL, although both papers were in Chinese.

Because TD Zhang’s papers from the 1970s to the early 1990s included a trace amount of mercury chloride, in addition to ATO (at a ratio of 1:100 by weight), strictly speaking, they had not proven that mercury chloride did not have a positive effect, despite the fact that their 1973 paper had indicated that only ATO was the effective ingredient in Ailin I.

In 1995 and 1996, Peng Zhang and colleagues from the same hospital as Tingdong Zhang published two papers which showed the effectiveness of ATO alone without mercury (Zhang et al., 1995, 1996). The 1995 paper was an abstract, which did not explicitly state that mercury chloride was not included in the 713 solution, although Zhang later said that they used only ATO. The 1996 paper did show that ATO, but not mercury chloride, was used. They treated 130 APL patients from 1992 to 1995, among which 72 went through one or more courses of treatment. A CR of 73% was observed in patients undergoing initial treatments and 52% in recurrent patients (Zhang et al., 1996).

In the process of uncovering the history of ATO research, we found no evidence that leukemia classification by traditional Chinese medical theories was useful for discovering the target of ATO. Here we separate traditional Chinese medicine into drugs and theories. Had the traditional Chinese medical theories (CMTs) been helpful for developing ATO as a treatment for leukemia? Zhang and colleagues discussed five types of leukemia based on CMT classification, there was no difference of ATO on different CMT types (Rong and Zhang, 1979; Zhang and Rong, 1979; Departments, 1984). In this regard, the Western classification of leukemia was helpful. When they completely gave up the CMT classification, the effect was more obvious. Interestingly, their first paper in 1973 did not mention CMTs, but their latter papers did. Lack of evidence for the utility of CMTs does not disprove the CMTs, but it is so far unclear whether the CMTs are important or essential for scientific studies of traditional Chinese drugs.

4 Chinese Contributions to APL Treatment

Anthracyclines (including daunorubin) and cytarabinebecame frontline treatment for APLbecause of research in the West (Ellison et al., 1968; Boiron et al., 1969; Bernard et al., 1973). Chinese contributions in the discoveries of ATO and ATRA came after those, but have significantly improved APL treatment. Here we place the Chinese discoveries in the historical context.

In 1973, Zhang and colleagues of China reported the therapeutic effect of ATO on leukemia (Zhang et al., 1973), and Zhang and Rong (1979) suggested that APL was particularly sensitive to ATO.

Collins, Gallo and Gallagher (1977) at the NCI successfully established a cell line (HL-60) from an APL patient. Collins et al.(1978) used it to screen for chemicals which could induce the differentiation of HL-60 cells to mature into normal cells. In 1980, Brietman, Selonick and Collins discovered that all-trans retinoic acid and 13-cis retinoic acid induced HL-60 differentiation into mature cells. Related chemicals such as Vitamin A was 1000 fold less effective. They suggested that “this compound could provide a new therapeutic tool in the treatment of acute myeloid leukemia”.

Breitman, Collins and Keene (1981) tested drug sensitivity of leukocytes from the peripheral blood of leukemia patients and found that cells induced to differentiate by ATRA all came from two patients with APL. Olsson and Brietman (1982) showed that retinoic acid could also induce U-937 lymphoma cells to differentiate. In 1983, Honma et al.from Japan reported the effects of multiple chemicals on inducing differentiation of cells from different leukemia patients, and found that ATRA was among those capable of inducing the differentiation of leukocytes from APL patients. Koeffler (1983) summarized in vitro studies including cellular differentiation by retinoic acid and other chemicals, viewing ATRA and 13-cis retinoic acid as equivalent in differentiating APL leukocytes.

Single cases of APL treatment by 13-cis retinoic acid were reported by four groups: Flynn et al. (1983) from Minnesota, USA; Nilsson (1984) from Lund, Sweden; Daenen et al.(1986) from the Netherland; and Fontana, Roger and Durham (1986) from West Virginia, USA.

In 1985, Zhen-Yi Wang of Shanghai Second Medical College could obtain ATRA (but not 13-cis retinoic acid) from a local source. He used it to successfully treat a five year old girl. In 1987, his group published a paper in the English edition of the Chinese Medical Journal, reporting the use of ATRA (alone or in combination) for the treatment of six APL patients(Huang et al., 1987). In 1988, Wang’s group published their use of ATRA in the treatment of 24 APL patients in Blood(Huang et al., 1988).It cited Breitman, Selonick, Collins (1980), Brietman, Collins, Keene (1981) and Koeffler (1983)，which reported the effects of ATRA and 13-cis retinoic acid on inducing the differentiation of leukemia leukocytes, as well as Flynn et al.(1983),Nilsson (1984), Daenen et al.(1986), and Fontana et al.(1986) which reported treatment of APL patients by 13-cis retinoic acid.

Huanget al.(1988), but not Huang et al.(1987) (both in English, but the the 1988 paper published in the US and the 1987 paper in China), drew international attention. Direct communication with French doctors also helped. The finding of the Wang group with ATRA were soon replicated. Chomienne et al.(1989) from France compared the effects of ATRA and 13-cis retinoic acid with two APL patients for each chemical and felt that ATRA were more effective. In 1990, the same French group, after working with leukocytes from 22 APL patients in vitro, concluded that ATRA was 10 times more effective than 13-cis retinoic acid (Castaigne et al., 1990). The effect of ATRA was also confirmed by Chinese doctors (e.g., Chen ZX et al., 1991). Warrell et al.(1991) in the US replicated the findings of the Wang group in China and the Degos group in France with 9 out of 11 APL patients successfully treated by ATRA. Since then, ATRA was well recognized for APL treatment. Tallman et al.(1997) reported their studies of 346 APL patients, in which they compared the therapeutic effects of ATRA and the previously standard chemotherapy with daunorubin and cytarabine, and found it to be more effective if ATRA was used for both induction and maintenance.

Duanet al.(1992) published in vitro studies of the effect of ATO on leukemic cells. Huang and coworkers from Dalian, China reported that a tablet with multiple components derived from traditional Chinese medicines (herbs and minerals) led to 98% CR in 60 APL patients (Huang et al., 1995). One of the components contained arsenic disulfide.

In 1995 and February 1996, Peng Zhang and colleagues from Harbin reported their success in using ATOalone in achieving 73% of CR in 130 APL cases from 1992 to 1995. No cross-resistance was observed between ATOand ATRA (Zhang et al., 1995, 1996).

In August, 1996, Guoqiang Chen and 18 other authors (including Tingdong Zhang in the middle and Saijuan Chen, Zhen-Yi Wang and Zhu Chen as the last authors) reported work from Shanghai Hematology Institute that used in vitro culture leukemic cells for mechanistic studies of the therapeutic effect of ATOon leukemia at the molecular level (Chen et al., 1996).

In 1997, Jingshu Xu, Jingmian Duan, Ying Xu, Xiaomin Xin, Xiaohong Song and Tingdong Zhang reported a case of who had recurrent APL three times (Xu et al., 1997). The patient was treated with Ailin I every time and had survived for 20 years.

Chenet al.(1997) from Shanghai published dose-dependent effect of ATO on leukemic cells in vitro. Shen et al.(1997) from Shanghai reported that they used pure ATOto treat 15 APL patients, among which 10 cases with only ATO. CR was achieved in 90%.

Soignetet al.(1998) from the Memorial Sloan-Kettering Cancer Hospital and Cornell Medical College reported in the New England Journal of Medicine(NEJM) that they had treated 12 recurrent APL cases with ATO and observed CR in 11 cases. The mechanisms were thought to be partial cellular differentiation and apoptosis.

The NEJMpaper helped general international acceptance of ATOas a treatment of APL, which could not be achieved by many papers published in China by Chinese doctors over the previous two decades.

5 Lack of Recognition

ATO has now been well accepted (and generally used) nationally and internationally, saving lives in China and other countries. However, the discoverer remains largely unknown in academic and medical communities, although there was a 2001 story about him in the New York Times(Rosenthal, 2001). It is more striking that, while the discovery of the effect of ATRA on APL has led to both national and international awards to Zhen-Yi Wang, not a single national or international award has been given to Tingdong Zhang or any of his Harbin colleagues for the discovery of the therapeutic effect of ATO on APL, although ATO was discovered more than a decade before ATRA and is recognized as “the most biologically active single drug in APL” by International Leukemia Experts for the European LeukemiaNet (Sanz et al., 2009).

The reason for lack of recognition is not due to controversies. There was a patent contention by Hongde Sun, a member of Zhang’s group. It was quite late and the judge ruled in Zhang’s favor. Peng Zhang insisted that he was the first to show the effect of ATO alone, without mercury. Tingdong Zhang and Rong (1979) had suggested that ATO alone was effective, but they had not shown data with ATO alone. Both Sun and Peng Zhang have made important contributions, but it is clear that Tingdong Zhang has played an undisputed key role in his persistent work from the 1970s to the early 1990s which turned the often fuzzy arsenic treatment with variable results into practically useful treatment with beneficial effects.

Guoqiang Chen, Saijuan Chen, Zhen-Yi Wang and Zhu Chen (1998) published in a Chinese journal that “from the early 1970s, Harbin Medical University discovered through clinical practices that arsenic trioxide could effectively treat APL. In the past two years, we have collaborated with HMU and used arsenic trioxide solution to treat APL patients resistant to ATRA and conventional chemotherapy”, affirming the work and priority of Harbin, though Zhang’s name and papers in the 1970s did not appear in the review (Chen et al., 1998).

Almost no English paper realized that Zhang had published his findings from 1973 to 1979. English papers, including those by Chinese scholars, only cited Sun et al.(1992) and sometimes Peng Zhang et al.(1996) as the first paper(s) for ATO treatment of leukemia. For example, Soignet et al.(1998), which replicated the findings of Zhang in the 1970s and played a major role in the international acceptance of ATO treatment for APL, mentioned “recent Chinese reports” of CR in APL by ATO, and cited only Sunet al.(1992), Peng Zhang et al.(1996), and Shen et al.(1997). It is impossible to know from the NEJMpaper that the original findings were made in the 1970s by Tingdong Zhang because both the tone and the citations made it seem that Chinese discoveries were made in the 1990s.

A news report in Sciencedid mention Zhang (Mervis, 1996), but stated that Zhang published his paper in 1992.

Zhang has published few English papers. In 2001, he and Guoqiang Chen were co-first authors (with Zhen-Yi Wang, Saijuan Chen in the middle and Zhu Chen as the corresponding author) of a review about ATO in an international journal Oncogene(Zhang et al., 2001). In the introduction, they stated “recent” studies of ATO treatment of APL, citing Chen et al.(1996). On the second page, they stated that the research on ATO began in 1971, without citing any publications, and that they had treated more than a thousand patients of different types of cancers including “chronic granulocytic leukemia, lymphoma, esophageal cancer, and particularly APL”, but again without citing any literature. Thus, Zhang, presumably as the first author of an English paper, neglected to cite his own early papers, effectively burying the pioneering findings in 1970s.

In 2002, Jun Zhu, Zhu Chen,Lallemand-Breitenbach and de The published a review in Nature Reviews Cancer. In the figure illustrating milestones in APL treatments, Tingdong Zhang in the 1970s were placed, but the citation in the text was Sun et al.(1992) and the explanation in the reference list credited Sun et al.(1992) as “first report of As2O3therapy in APL”.

Both Sun et al.(1992) and Zhang et al.(1996) were published in Chinese, and neither of them cited papers from the 1970s. Thus, even if any international scholars attempted to obtain English translations of the 1992 and 1996 papers, they would not know the original 1970 papers.

In 2008, Zhen-Yi Wang and Zhu Chen reviewed progresses in APL treatment in Blood, with its first citation of ATO as the Zhu et al.(2002) review, andfurther citations for ATO treatment of APL being Sun et al.(1992), Zhang et al.(1996), Chen et al.(1996), Shen et al.(1997) and Niu et al.(1999).

Chen et al.(2011) published a review of the therapeutic effect of ATO on leukemia, which stated “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”, without mentioning the researchers or citing papers of the 1970s. The review then cited Sun et al.(1992) for showing “that Ailing-1 induced CR in 21 of 32 patients with APL with an impressive 10-year survival rate of 30%” before stating that “the efficacy of pure ATO in treating relapsed APL was then reported by Shanghai Institute of Hematology (SIH) in 1996-1999”, citing their own papers including Shen et al.(1997) and Niu et al.(1999), ignoring the papers of Peng Zhang et al.from Harbin Medical University who had published a paper in 1995 and one in 1996, which stated that they had used ATO alone (without a trace amount of mercury chloride). According to a 2013 blog by Peng Zhang, his results were known to Chen and others who attended a national meeting in 1995 (Zhang, 2013). However, by ignoring Zhang Peng and colleagues, the Shanghai authors (Chen et al., 2011) gives the impression that pure ATO was first used by Chen and colleagues in Shanghai Institute of Hematology.

A 2011 paper on a ten-year follow-up study of ATO treatment of APL published by Au et al.from Hong Kong cited a paper published by US authors in 2001.

Thus, no authors who can read Chinese have cited any of the 1970s papers in their English publications. In the current climate that English authors do not go to original papers in even French or German, it is no wonder that they do not know the titles and authors of the original papers published in Chinese. The contributions of Tingdong Zhang and the precise timing of his discovery are therefore virtually unknown in the international academic and medical communities.

6 Implications of Paying Attention to Work Published in Chinese

In the past, there is a general negligence of clinical studies carried out in China. Language is only part of the reason. With the large number of patients in China, many doctors in China have more clinical experience than most doctors in Western countries. Some, even though a small fraction of, Chinese doctors may have insights into treatments that they have only published in Chinese journals. These seem worth further tests and validations.

In the case of ATO, for example, Chinese doctors including Zhang and others have reported ATOtreatment of multiple cancers, from liver, stomach and colon cancers to lymphomas (Li et al., 1988; Liu et al., 2005; Guo et al., 2006).

An indirect inference is that rigorous studies of components of Chinese medicines may lead to more discoveries. For example, drugs used tentatively by Chinese hospitals or marketed aggressively by Chinese companies (without prior stringent tests), may prove to be more powerful and specific after rigorous studies, and become more internationally acceptable and eventually help more patients and save more lives.

Acknowledgements

YR thanks Lianda Li (李连达) of the Chinese Academy of Traditional Medicine for bringing him to the attention of two papers (Guan 1958, and Chaoyang People’s Hospital, 1972), and the work of Aixiang Zhou （周霭祥）and Deqin Gu（顾德馨）.

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英文版：

http://link.springer.com/content/pdf/10.1007%2Fs11427-013-4487-z.pdf

中文版：

http://life.scichina.com:8082/sciC/CN/abstract/abstract511111.shtml#

张亭栋等研究三氧化二砷治疗急性早幼粒细胞白血病的部分论文

Treatment of acute promyelocytic leukemia (APL) has been significantly improved through the introduction of cytarabine by Ellison et al.in 1968, daunorubicin by Boiron et al.in 1969, arsenic trioxide by Zhang et al.in 1973 and all-trans retinoic acid by Huang et al.in 1987.

Least known among these is the pioneering research of Dr. Tingdong Zhang and colleagues: not a single English paper has cited their important original papers on arsenic trioxide in the 1970s.

To help alleviate this problem, I have listed here some of the publications of Dr. Zhang and his colleagues，with links to PDF files. I recommend that future publications on APL or arsenic trioxide cite Zhang et al.(1973) and Zhang and Rong (1979).

It should be clear from the documented literature that Tingdong Zhang played a pivotal role throughout these studies, with different collaborators contributing to some aspects, but not all, of this line of research. Only Zhang contributed to every key step of this work as well as the entire project.

There have been efforts in China to use traditional Chinese medical recipes that contain arsenic sulfate, but to date, the recipes have not been reduced to single chemicals and the exact relationship of those recipes to arsenic trioxide remains unclear. Thus, work by Zhang and colleagues on arsenic trioxide stands out from these other efforts in its singular success of transforming multiple starting materials into a defined molecule.

What follows are the information for citation, PDF files, brief summaries and background of some of the major papers.

早幼粒细胞白血病APL的治疗有显著改善，归功于Ellison等（1968）引入cytarabine，Boiron等（1969）引入daunorubicin，张亭栋等（1973）引入三氧化二砷，王振义课题组以黄等（1987）发表的论文引入全反型维甲酸。

这些工作中最不为人所知的是张亭栋医生和同事的先驱工作：没有一篇英文论文引用他们在1970年代发表的、有关三氧化二砷的重要原始论文。

为减轻这一问题，我在此列出张亭栋医生和同事的部分文章，并提供PDF链接。我建议未来的有关文章引用张亭栋等（1973），张亭栋和荣福祥（1979）两篇论文。

有据可查的文献很清晰地显示，张亭栋在这一工作中起了关键作用，不同的合作者对一些不同方面有贡献，但只有张亭栋对该研究的整体、和每个关键步骤都有贡献。

中国另有使用含雄黄的复方的工作，迄今未化解为单体化合物，并不清楚起作用的化学成分，迄今它们与三氧化二砷的关系仍然不明。因此，张亭栋与同事的工作也突出于这些工作，因为只有张亭栋等的工作从多种材料中定义了单个分子。

以下为部分关键论文的引用信息，PDF文档，和内容、背景简介。

Zhang TD, Zhang PF, Wang SR, and Han TY (1973). Preliminary clinical observations of 6 cases of leukemia treated by “Ailin solution”. Med Pharm Heilongjiang1973(3):66-67 (张亭栋,张鹏飞,王守仁,韩太云(1973) “癌灵注射液”治疗6例白血病初步临床观察. 黑龙江医药1973(3):66-67).

PDF：1973 Zhang TD_ Zhang PF_ Wang SR_ and Han TY.pdf

Summary and Background

In this paper, Zhang TD, Zhang PF, Wang and Han reported that they had used “Ailin solution” (also known as “Ailin I”) to treat six cases of chronic granulocytic leukemia. It explicitly stated that the components of the solution were arsenic trioxide and a trace amount of mercury chloride. All six improved after the treatment. It also mentioned that the authors were testing acute leukemia patients

Before this paper, Taiyun Han, a pharmacist at the First Affiliated Hospital of Harbin Medical University, had learned that a country doctor practicing traditional Chinese medicine had used a combination of arsenic,mercury and toad venom to treat lymphatic tuberculosis and cancers. In March 1971, Han dissolved the three components in a solution, which he called“713” (after the year and month of his preparation) or “Ailin (literally meaning cancer effective)”. This was injected intramuscularly into patients, showing effects in some cancer patients. It was hotly sought after by local population, but soon abandoned because of its toxicity. Han neither defined the exact disease(s) that Ailin was against nor revealed the effective chemical component in Ailin.

Tingdong Zhang was a medical doctor in the same hospital as Han. Zhang was initially asked by the Health Bureau of Heilongjiang province to examine the validity of the claims of the countryside practitioner and later collaborated with Han.

This paper was thus a collaboration of Zhang, Han and others. On the one hand, rather than working with a variety of diseases ranging from tuberculosis to multiple types of cancers, Zhang et al.(1973) targeted leukemia. On the other hand, Zhang et al.(1973) used blood analysis, elevating the standard for measuring treatment success, which was not used by country practitioners of traditional Chinese medicine.

张亭栋、张鹏飞、王守仁、韩太云在本文中报道他们用“癌灵注射液”（以后也称“癌灵1号”）治疗6例慢性粒细胞白血病病人。他们明确知道主要用了砒霜的化学成分“亚砷酸（三氧化二砷）”和微量“轻粉（氯化低汞）”。经过治疗，6例病人症状都有改善，其中一例为慢性白血病发生急性变的患者也有效。该文还提到作者们还在研究对急性白血病的治疗效果。

此前，哈尔滨医科大学第一附属医院的药师韩太云得知民间中医用砒霜、轻粉（氯化亚汞）和蟾酥等治疗淋巴结核和癌症。1971年3月，韩太云将它们改制水针剂，称"713"或"癌灵"注射液，通过肌肉注射，对某些肿瘤病例见效，曾在当地风行一时，但因毒性太大而放弃。韩当时没有确定癌灵适用的特异疾病、亦未确定癌灵几种成分中何为有效成分。

张亭栋是同一医院的医生，黑龙江省卫生厅曾请他检查农村中医声称的医疗效果。1972年，张亭栋与韩太云合作。张亭栋等一方面主要集中做白细胞，而非无选择地将药物用于从结核到多种癌症等很多疾病，另一方面，张亭栋等用血象分析等可靠的客观标准检测治疗效果,而乡村中医无此标准。

Departments of Traditional Chinese Medicine and Laboratory Medicine of the First Affiliated Hospital of Harbin Medical University (1974). Therapeutic observations of 17 cases leukemia treated with Ailin No.1 and dialectic theory. J Harbin Med Univ1974(2):25-30 (哈医大一院中医科，哈医大一院检验科(1974). 癌灵1号注射液与辨证论治对17例白血病的疗效观察. 哈医大学报1974(2):25-30).

PDF:1974 癌灵1号注射液与辨证论治对17例白血病的疗效观察哈医大学报25-30.pdf

Summary

This paper summarized the treatment of 17 cases of leukemia patients from January 1973 to April 1974. After going through different types of leukemia,they reported that Ailin I was effective in treating multiple types of leukemia, leading to complete remission in acute leukemia patients.

In a separate 1976 paper not listed here, they used institutional authorship to publish a report on five cases of acute leukemia in which they had achieved complete remission.

本文总结从1973年1月至1974年4月对不同类型白血病的治疗效果，发现“癌灵1号”对多种白血病有效、对急性白血病可以达到完全缓解。

另外，没有在此例出的一篇相关文章是：1976年哈医大一院中医科曾撰文“中西医结合治疗急性白血病完全缓解五例临床纪实”，介绍5例经治疗后完全缓解的患者的诊治过程及各种临床表现。

Rong FX and Zhang TD (1979). A report on long term survival of 2 cases of acute granulocytic leukemia. J New Med Pharm1979(6):31-34 (荣福祥,张亭栋(1979).急性粒细胞性白血病长期存活2例报告. 新医药学杂志1979(6):31-34).

PDF:1979 Rong & Zhang 急性粒细胞性白血病长期存活2例报告.pdf

Summary:

This paper reported two acute granulocytic leukemia cases, one with complete remission for four and half and the other for three years

本文报道“癌灵1号”治疗后存活4年半和3年的两例病人，皆为急性粒细胞性白血病。

PDF:1979 Zhang & Rong 癌灵一号注射液与辨证论治治疗急性粒细胞型白血病.pdf

Summary:

This paper summarized 55 cases of acute leukemia. 23 patients were treated with Ailin I alone (from 1973 to 1974), 20 patients treated with Ailin I in combination with Western chemotherapy and other Chinese medicines from 1975 to 1976, and 12 cases treated with Ailin I plus other Chinese medicines and chemotherapy from 1977 to 1978. For each patient, the authors presented leukemia subtypes and clinical observations. All 55 cases improved to some extent, with a remission rate of 70% and with complete remission in 12 cases. The side effect was small with the doses they used. The authors then applied 10 times the equivalent of what they used for adult human patients into 12 rabbits. No toxicity was observed in the heart, the liver,the spleen or the kidney of the rabbits.

Zhang and Rong (1979) explicitly stated that：1）significant improvement was observed in three patients（one adult and two children）treated with only Ailin I, but no other Western or Chinese drugs. At the time of publication, the children had survived for more than 4 years and the adult more than 9 months. When using other Chinese medicines, Zhang and Rong pointed out that those were not used for treating leukemia, but for supporting the general health of the patients so that they could tolerate more treatment; 2）the effective component of Ailin I was arsenic trioxide (on page 11 of their paper); 3）acute granulocytic leukemia (M3 type of the French-American British FAB classification, also known as APL) was the most sensitive to the treatment, which they reiterated on pages 10 and 11.

Therefore, it can be concluded that, by 1979, Zhang and his collaborators had clearly reached our current understanding: that arsenic trioxide can treat leukemia, especially the M3 subtype or APL.

Zhang et al.(1973) was the pioneering paper, beginning to study the effect of arsenic trioxide on leukemia (but tested only chronic leukemia), while Zhang and Rong (1979) was the most representative paper. Zhang and Rong (1973) made it clear that 1) only arsenic trioxide was required for the treatment; 2) the most sensitive leukemia was the M3 subtype of leukemia (also known as APL).

While different collaborators were involved in 1973, 1974 and 1979, only Tingdong Zhang was always involved and was always a major author, thus establishing his key role in this series of research.

1979年张亭栋和荣福祥总结他们从1973年至1978年治疗急性粒细胞型白血病共55例。其中1973年至1974年单用“癌灵一号”治疗23例，1975年至1976年用“癌灵一号”加其他中药和少量化疗药物治疗20例，1977年至1978年用“癌灵一号”加其他中药和加少量化疗治12例。对每一个病例，他们都根据血象分型，有明确的疗效观察。全部55例都有不同程度的好转，缓解率70%，12例完全缓解，对病人的毒副作用小。他们还用十倍于成人的剂量，给12只家兔注射“癌灵一号”，未见心、肝、脾、肾毒性作用。

张亭栋和荣福祥（1979）明确指出：1）有三例病人（一位成人、两位儿童），单纯使用“癌灵一号”，不用其他中药、不用化疗西药，也显示疗效，其中当时儿童存活已经4年，成人已存活9个月。在使用其他中药时，他们也指出其他中药并非治疗白血病、而用来支撑病人身体状况；2）在第11页，他们指出“癌灵一号”之有效成分为三氧化二砷；3）在第10页和第11页，他们两次明确指出对早幼粒型白血病效果最好。也就是说，1973年到1979年，张亭栋与不同的同事合作发表的论文，清晰地得到了我们今天的认识：三氧化二砷可以治疗白血病，特别是急性早幼粒白血病（法国-美国-英国FAB分型的M3型白血病，也即acute promyelocytic leukemia，APL）。

1973年的论文是他们发现“癌灵一号”的开创性论文，开始将砒霜用于白血病（但当时只报道了慢性白血病），而张亭栋与荣福祥（1979）是他们这一系列工作的代表性论文。张亭栋与荣福祥（1979）论文已经明确：1）癌灵一号只需要三氧化二砷起治疗作用；2）最敏感的白血病是M3型的急性粒细胞白血病（后来也称为APL）。

有不同的合作者参与1973、1974、1979年发表的工作，而张亭栋自始至终参与，并作为主要作者，所以发表的文献清晰地表明张亭栋的关键作用。

Department of Traditional Chinese Medicine of the First Affiliated Hospital of Harbin Medical University (supervisor Zhang TD, writers Li YS, Hu XC, participants Li MX, Zhang PF, Rong FX, Sun HD, Li HR, Wu YX) (1981) A clinical summary of 73 cases treated by Ailin No.1 combined with the dialectic theory. Chinese Medicine and Pharmacy of Heilongjiang1981(4):28-30 (哈尔滨医科大学附属第一医院中医科（指导:张亭栋执笔: 李元善胡晓晨参加人:李明祥张鹏飞荣福祥孙洪德李会荣吴云霞检验科血研究室）（1981）癌灵一号结合辨证施治治疗急性粒细胞型白血病73例临床小结. 黑龙江中医药1981(4):28-30).

PDF:1981 癌灵一号结合辨证施治治疗急性粒细胞型白血病73例临床小结.pdf

Summary and background:

This paper, though under an institutional authorship, came with a footnote indicating Zhang as the supervisor (with 8 other authors). It reported 73 cases of acute granulocytic leukemia patients, with complete remission of 24% and remission rate of 86%。

Not listed here is a related report in 1982, in which Zhang and Li presented a report to a national meeting on 22 cases of complete remission by Ailin I and on 98 cases of non-lymphatic leukemia.

1981年哈尔滨医科大学附属第一医院中医科（文章最后注脚标明指导：张亭栋；执笔：李元善，胡晓晨；参加人：李明祥，张鹏飞，荣福祥，孙洪德，李会荣，吴云霞，检验科血研究室）报道“癌灵一号”对急性粒细胞白血病完全缓解率达24%、总缓解率达86%。

在此未列出来，另外在1982年的全国中西医结合治疗白血病座谈会上，张亭栋、李元善交流了“癌灵1号治疗急性粒细胞白血病临床实验研究—附22例完全缓解分析”和“98例非淋巴细胞白血病分型与临床疗效探讨”。

Zhang TD (1982). Comments on questions about designing clinical research with combined Chinese and Western medicine. J Integrat Trad Chin West Med2:180-181 (张亭栋（1982）谈谈中西医结合临床科研设计中的几个问题. 中西医结合杂志2:180-181).

PDF:1982 Zhang 谈谈中西医结合临床科研设计中的几个问题.pdf

Zhang published a commentary on his work.

Zhang TD (1983). Understanding and treatment of leukemia by Chinese Medicine. J Trad Chin Med1983(3):71-74 (张亭栋（1983）中医对白血病的认识和治疗. 中医杂志1983(3):71-74).

PDF:1983 Zhang 中医对白血病的认识和治疗.pdf

Zhang published a commentary on leukemia treatment.

Zhang TD, Li YS (1984). Clinical findings and experimental research of Ailin No. 1 in treating acute granuloleukemia. J Integrat Trad Chin West Med 4:19-20 (张亭栋,李元善(1984). 癌灵1号治疗急性粒细胞白血病临床发现和实验研究。中西医结合杂志4:19-20).

PDF:1984 Zhang & Li 癌灵1号治疗急性粒细胞白血病临床分析及实验研究.pdf

Summary:

Zhang and Li published a summary of 81 cases whom they had treated since 1971. Among the 22 cases of complete remission, they pointed out that 7 were of the M2 type and 15 were of the M3 type. They again stated that the effect on M3 type were particularly obvious.

张亭栋和李元善(1984)总结他们1972年以来治疗的81例急性粒细胞白血病，分析其中完全缓解的22例。他们指出，完全缓解的22例中，7例为M2型，15例为M3型白血病。他们也再次指出“以M3型效果尤为显著”。

Zhang TD (1985). Diagnosis and treatment of acute non-lymphatic leukemia. J Integrat Trad Chin West Med5:713 (张亭栋（1985）急性非淋巴细胞性白血病证治. 中西医结合杂志5: 713).

Zhang published another paper on the effect of Ailin I on non-lymphaticacute leukemia.

Sun HD Ma L Hu XC Zhang TD, Rong FX, Wang QH, Li JM and Feng XQ (1991). Areport on 16 acute promyelocytic leukemia cases of long term survival treated by Ailin No.1 in combination with traditional Chinese dialectic theories. Info Trad Chin Med Pharm1991(6):39-41 (孙鸿德,马玲,胡晓晨,张亭栋,荣福祥,王钦华,李金梅,冯秀芹(1991) 癌灵1号结合中医辨证施治急性早幼粒白血病长期存活16例报告. 中医药信息1991(6):39-41).

PDF:1991 Sun et al 癌灵1号结合中医辨证施治急性早幼粒细胞白血病长期存活16例报告.pdf

Summary:

Sun, Ma, Hu, Zhang, Rong, Wang, Li and Hong reported 16 cases of APL. This was a continuation of Zhang and Li (1984). It reported that Ailin I had been used to treat 32 APL cases from 1974 to 1985, with complete remission in 19 cases and that 16 cases had survived for more than 5 years.

孙鸿德、马玲、胡晓晨、张亭栋、荣福祥、王钦华、李金梅、冯秀芹发表“癌灵1号结合中医辨证施治急性早幼粒白血病长期存活16例报告”，应该是延伸1984年张亭栋和李元善的文章。他们报道从1974年到1985年以“癌灵一号”治疗急性早幼粒白血病32例，19例完全缓解，16例存活超过五年。

Sun HD Ma L Hu XC Zhang TD (1992). Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integrat Chin & West Med12:170-172 (孙鸿德,马玲,胡晓晨,张亭栋(1992).癌灵1号结合中医辨证治疗急性早幼粒白血病32例. 中国中西医结合杂志12:170-171).

PDF:1992 Sun et al 癌灵1号结合中医辨证治疗急性早幼粒细胞白血病32例.pdf

Summary:

Sun, Ma, Hu and Zhang published this short paper as “Sharing Experience”,reviewing materials identical to those in the 1991 paper. Strangely, most English papers cite this 1992 paper for the discovery of arsenic trioxide treatment of APL. Both the 1991 and the 1992 papers were in Chinese. The key findings were published in Zhang et al.(1973) and the effect on APL was clear in Zhang and Rong (1979). The often cited 1992 paper of Sun et al.(1992) was not substantially different from that of 1979, in either the chemicals applied or the subtype of leukemia treated. There is no scientific reason why Sun et al.(1992) was cited instead of the other papers prior to 1992.

孙鸿德、马玲、胡晓晨、张亭栋这篇作为“经验交流”发表的短文，实质相同于1991年论文。比较奇怪的是，英文文献引用这篇文章。该文与1991年论文一样都是中文，内容不过是1991年论文的简介，而实际发现最早发表于张亭栋等（1973），到张亭栋和荣福祥（1979）已明确了对APL的作用最好。而1992的论文在本质上与1979年的文章无差别，既没有改变所用的药物成分、也没有改变适应症。没有科学理由引用孙鸿德等（1992）而不引用张亭栋等（1973）、或张亭栋与荣福祥（1979）。

Zhang P, Wang SY, Hu LH, Shi FD, Qiu FQ, Hong LJ, Han XY, Yang HF, Song YZ,Liu YP, Zhou J, Jin ZJ (1996) Treatment of 72 cases of acute promyelocytic leukemia with intravenous arsenic trioxide. Chin. J. Hematol. 17:58–62 (张鹏,王树叶,胡龙虎,施福东,邱凤琴,洪珞珈,韩雪英,杨惠芬,宋颖昭,刘艳平,周晋,金镇敬（1996）三氧化二砷注射液治疗72例急性早幼粒细胞白血病.中华血液学杂志17:58-60).

PDF：1996 张鹏et al 三氧化二砷注射液治疗72例急性早幼粒细胞白血病.pdf

Summary：

Peng Zhang et al.from the same hospital as Tingdong Zhang published their use of arsenic trioxide in treating 72 APL cases. It summarized their experience of using arsenic trioxide alone (without a trace amount of mercury) in 130 APL cases from 1992 to 1995, among which 72 went through one or more course of treatment. A complete remission of 73% was reported for patients undergoing initial treatments and 52% in recurrent patients. No cross-resistance was observed between arsenic trioxide and all trans-retinoic acid.

哈尔滨医科大学第一临床医院的张鹏、王树叶、胡龙虎、施福东、邱凤琴、洪珞珈、韩雪英、杨惠芬、宋颖昭、刘艳平、周晋、金镇敬(1996)总结他们自1992年至1995年用三氧化二砷（不含汞）治疗130例APL病人中完成一个及以上疗程的72例。初治患者完全缓解率为73%，复发患者完全缓解率为52%，与全反式维甲酸无交叉耐药。

Liu LX, Zhu AL, Chen W, Guo HX, Wang XQ, Liu ZH, Zhang TD, Jiang HC, Wu M(2005). Effect of arsenic trioxide on hepatocellular carcinoma and its mechanistic studies. Chin J Surg43:33-36.(三氧化二砷治疗肝细胞肝癌及其机理研究. 中华外科杂志43:33-36）

PDF：2005 三氧化二砷对原发性肝癌的作用及其机理研究.pdf

Guo HX, Chen W, Liu LX, Zhang TD (2006). Recent status of the effect of arsenic trioxide on colon cancer. Chin J Integr Trad West Med Dig14:207-209.（三氧化二砷治疗结肠癌现状中西医结合杂志14:207-209）

PDF：2006 三氧化二砷对结肠癌作用的研究近况.pdf

张亭栋与王振义的同类工作

药用化学分子

对于新药的研究，可以比较我国发现过多少新药，多少个化学单体是因为中国的工作而被全世界应用，我国发明的药物对治疗某个疾病带来多大的推动，我国发明的药物治疗了多少病人，等。

陈克恢于1920年代在协和研究麻黄素代表了中国现代药物研究初期的高度。从单分子化学药物角度来说，青蒿素、三氧化二砷和全反型维甲酸无疑是一个世纪以来我国最为突出的工作，它们都是因为中国的关键工作，得以治疗全世界相关的病人，而且迄今仍为我国新药研究和医学疗法希望达到和超越的标杆。

如果比较最突出的青蒿素、三氧化二砷和全反型维甲酸三个药物，青蒿素的工作包括从植物提取新的活性分子，发现新的化学结构。三个药物都有前人工作，青蒿素和三氧化二砷起源于中药的提示，全反型维甲酸起源于西方国家研究的提示。其中，青蒿素与原有知识的距离最远，因为青蒿、黄蒿治疗疟疾在中药并非常用，具体制剂不清楚，《本草纲目》记录的多个制作方法中有些必定灭活青蒿素而无用，民间方剂也鱼龙混杂、无清晰结论。因此，发现青蒿素的工作是同一领域中推动最大的一步。所以，在中国近代化学药物发现中，青蒿素的工作最优。目前我国尚不能做很多这样工作，与国际先进水平还有很大差距，我们自然希望中国将有更多的像青蒿素一样的工作。

评价三氧化二砷与全反型维甲酸的工作，必需清楚现状：我国用的化学药物绝大多数都是抄来的，我国发明和发现了新的药用分子，我国审批机构更是发了很多新药证书，但真正能获得（无论是国内还是国外）医生和市场认同的新药则极少。今天所谓我国的创新药物中多数也以仿造为主，由于我国的关键贡献而导致世界用某种化学药物的例子极少。所以，三氧化二砷与全反型维甲酸确实是我国在化学药物方面突出的两项工作。上海交通大学医学院（原上海第二医学院）的王振义教授因为发现全反型维甲酸治疗APL亚型白血病而获得国内外认可（包括1994年当选中国工程院院士、1994年美国通用汽车癌症奖、2011年中国最高科学奖），是完全应该的，因为他的工作在我国发现药物治疗作用方面非常突出，且造福世界。

APL亚型白血病的治疗

对于新药的研究，纵向是比较同一疾病、或同一药物，我国的工作起了多大的作用。因为三氧化二砷和全反型维甲酸治疗的是同一疾病，所以，较为方便进行纵向（和小范围的横向）比较。

白血病可分为多种亚型，其中一种为“急性早幼粒白血病”（APL，亦称FAB分型的M3型）。1968年，Ellison等报道用阿糖胞苷治疗APL成功。1969年，Boiron等报道用柔红霉素（daunorubin）治疗APL，1973年Bernard等总结了他们1967年以来用柔红霉素的成功率。包括柔红霉素的蒽环类抗生素(anthracyclines)和阿糖胞苷为APL化疗的标准药物。

在中国的工作推广到世界后，现在国际上APL的常用疗法中三氧化二砷和全反型维甲酸赫然占重要地位，超过原有化疗药物（Sanz，2009；Tallman and Altman，2009；Estey，2011；Powell等，2010；Sanz和Lo-Coco，2011)。三氧化二砷被欧洲白血病国际联盟认为是“治疗APL最有生物活性的单个药物”（“the most biologically active single drug in APL”，Sanz et al.，2009)，被美国同行认为是治疗APL患者最有效的单个药物（“the single most active agent in patients with APL”，Tallman and Altman, 2009)。三氧化二砷和全反型维甲酸合并用药可能“在不久的将来在多数，如果不是全部APL患者中，替代常规疗法” （holds the promise to “replace conventional approaches for most, if not all, patients in the very near future”，Tallman and Altman, 2009)。近年的研究更见证了世界上广泛接受三氧化二砷治疗APL(Sanz and Lo-Coco 2011)，并继续有更多证据表明三氧化二砷对新诊断的和复发的APL都有治疗作用(Powell et al., 2011; Estey, 2011)。

三氧化二砷治疗APL

我们已在其他文章多次介绍过三氧化二砷的一些细节，此处仅列关键步骤。

从古代到1960年代，砒霜和三氧化二砷在中国和外国都有过应用，但其适应症不很明确，有时很泛，而砒霜毒性很大，所以没成为医生普遍接受的治疗某种疾病的标准药物，即使在有人试过的白血病，也未明确哪种白血病适用三氧化二砷。而有些用中药的疗法是合用砒霜和其他药物，不清楚其中有效成分。所以，在国外和国内，砒霜皆非一般医生用来治疗白血病的常规，更不知道APL对三氧化二砷最为敏感。

1973年，张亭栋、张鹏飞、王守仁、韩太云报道用癌灵一号治疗慢性粒细胞白细胞。1979年，荣福祥和张亭栋报道癌灵一号治疗两例急性粒细胞白细胞。1979年，张亭栋和荣福祥报道总结他们从1973年到1978年用癌灵一号治疗55例白血病患者。在这篇文章中，他们明确指出：只需三氧化二砷起治疗作用，无需其他中药、也无需其他化学成分；三氧化二砷治疗最有效的是急性早幼粒白血病（APL）。

1980、1990、2000年代，张亭栋和同事继续以此药治疗APL，不断证明其有效性。所以，在张亭栋等工作以前，含砒霜的复合药对疾病针对性模糊，而在张亭栋等1973和1979年的工作以后，才知道三氧化二砷是对APL有高度针对性的单一化学药物。

此后，张亭栋和同事的结论不断为其他医生验证和推广，例如1996年，哈尔滨医科大学第一附属医院的张鹏等总结他们1992年到1996年专门治疗130例APL患者。

1996年开始，上海第二医学院血液研究所也开始发表论文，介绍他们使用三氧化二砷的疗效和研究。陈竺曾在国际会议上介绍张亭栋，陈竺、陈赛娟、王振义等加入三氧化二砷的研究，国际上不断出现英文论文发表中国的研究结果。

1998年，国际权威医学刊物《新英格兰医学杂志》发表美国Soignet等验证三氧化二砷治疗APL的论文，这篇英文论文对三氧化二砷推广到全世界起的作用，是1970年代到1990年代张亭栋等中文文章无法做到，不过Soignet等并非突破而是验证中国的工作。

Soignet等美国医生不知道张亭栋的工作是1970年代做的，误认为中国的工作始于1990年代，他们称“中国的研究者最近报道”。他们未引用张亭栋等1970年代的工作，而引用：1）孙鸿德,马玲,胡晓晨,张亭栋（1992）；2）张鹏,王树叶,胡龙虎,施福东,邱凤琴,洪珞珈,韩雪英,杨惠芬,宋颖昭,刘艳平,周晋,金镇敬（1996）；3）沈志祥等（Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD张亭栋, Chen SJ陈赛娟, Chen Z陈竺, and Wang ZY王振义）（1997）；4）陈国强等（Chen GQ，Zhu J, Shi XG, Ni JH, Zhong HJ, Si GY, Jin XL, Tang W, Li XS, Xong SM, Shen ZX, Sun GL, Ma J, Zhang P, Zhang TD张亭栋, Gazin, Naoe T, Chen SJ陈赛娟, Wang ZY 王振义, Chen Z陈竺（1996）。

另外，上海血液研究所的Chen GQ等（1996）在《血液》发表的有关三氧化二砷的文章也未引用1970年代的张亭栋文章，引用了孙鸿德,马玲,胡晓晨,张亭栋（1992），称“recently”。上海血液研究所的Shen ZX等（1997）在其论文引言中说明1970年代中国东北发现，但引用的最早文献也是孙鸿德等（1992）。Chen GQ等（1997）的《血液》论文也引用孙鸿德等（1992）。

Chen GQ等（1996）、Shen ZX等（1997）、Chen GQ等（1997）和Soignet等（1998）四篇论文是1990年代中期对于国际上知晓三氧化二砷很重要的英文文献，但它们都无助于国际上得知张亭栋1970年代的文章。

实际上，直到三氧化二砷已经成为国际常用治疗APL药物的今天，中外作者的英文文章仍不引用张亭栋等1973和1979年的文章，包括近年综述也不引用，例如：Wang王振义and Chen陈竺（2008），Sanz等（2009），Tallman与Altman（2009），Powell等（2010），Sanz与Lo-Coco（2011），Chen陈赛娟, Zhou, Zhang, Mao, de Thé 与Chen陈竺（2011），Estey（2011）。

全反型维甲酸治疗APL

1977年，美国国立健康研究院国家癌症研究所肿瘤细胞生物学实验室的Steven Collins、Robert Gallo、Robert Gallagher报道他们从一位APL女性患者外周血获得细胞，进行培养后获得HL-60细胞系，第一次建立APL的体外细胞模型。1978年，Collins等鉴于前人对其他白血病细胞的研究，用多种化合物分别处理HL-60细胞，发现其中一些可以使HL-60癌细胞分化成为正常细胞。

1980年，Breitman、Selonick、Collins等发现，全反型维甲酸和13顺型维甲酸可以将HL-60分化成为正常的成熟白细胞，其他几种相近的化合物（包括维生素A等）作用低于维甲酸一千倍。他们在此文中提出，维甲酸可以提供一种治疗APL的新工具（“this compound could provide a new therapeutic tool in the treatment of acute myeloid leukemia”）。

1981年，Brietman、Collins、Keene等从21例白血病患者获得其外周血中的白细胞，在体外进行药敏检验，能够被全反型维甲酸诱导分化的白血病细胞都是来源于两例APL患者。1982年，Olsson和Brietman报道维甲酸也可以分化淋巴瘤细胞系U-937细胞。1983年，日本的Honma等报道多种化合物对不同白血病人来源的细胞在体外有诱导分化的作用，其中可以分化APL患者白细胞的化合物包括全反型维甲酸。1983年，美国洛杉矶加州大学的Koeffler 综述体外培养白血病细胞的研究，包括维甲酸在内的多种化合物有诱导分化作用，认为全反型维甲酸和13顺型维甲酸对APL细胞有同等作用。

1983年，美国明尼苏达大学Flynn、Miller、Weisdorf、Arthur、Brunning、Branda报道用13-顺维甲酸治疗一例APL患者，而且观察了其细胞在体外的分化。

1984年，瑞典Lund大学医院内科的Nilsson用13-顺维甲酸治疗一例其他化疗后复发的APL患者。

1986年荷兰的Daenen、Vellenga、van Dobbenburgh和Halie报道用13-顺维甲酸治疗一例APL。

1986年美国西弗吉尼亚大学的Fontana、Roger, Durham报道用13-顺维甲酸治疗一例APL。

1987年，中国上海第二医学院王振义课题组以黄萌茸为第一作者在《中国医学杂志》发表文章，报道使用全反型维甲酸（合并阿糖胞苷或单独用药）对APL的治疗作用。据上海交通大学王振义网页显示，这项工作早在1985年王振义课题组用全反型维甲酸成功地治疗了一例APL患者（所以当时应该不知道国外1986年两篇13顺维甲酸的文章）。据王振义和陈竺（2008）报道，1980年代中期用全反型维甲酸是因为当时上海有的维甲酸是全反型，而且当时上海市允许用全反型维甲酸治疗皮肤病。1988年，王振义课题组以黄萌茸等在国际血液方面权威学术刊物《血液》报道他们用全反型维甲酸成功治疗24例APL患者。该文引用了Breitman, Selonick, Collins（1980）、Brietman, Collins, Keene（1981）以及Koeffler（1983），这些文章研究（和综述）全反型和13顺维甲酸在体外对白血病细胞诱导分化作用。黄萌茸等（1988）也引用了Flynn等（1983）、Nilsson（1984）、Daenen等（1986）、Fontana等（1986）文章，这些文章是国外将13顺维甲酸用于治疗APL患者。也就是说，王振义课题组在国外这两个系列的工作基础上，开展了自己的工作，成功地证明全反型维甲酸可以用于治疗APL患者。

1989年，在王振义工作的基础上，法国的Chomienne、Ballerini、Balitrand、Amar、Bernard、Boivin、Daniel、Berger、Castaigne和Degos用13顺维甲酸治疗2例APL患者、用全反型维甲酸治疗2例患者，初步对照感到全反型维甲酸的疗效大于13顺维甲酸，他们在体外对培养细胞进行比较也发现全反型维甲酸作用大于13顺维甲酸。1990年，法国的Castaigne、Chomienne、Daniel、Ballerini、Berger、Fenaux、Degos等用全反型维甲酸治疗了22例APL。1990年，法国的Chomienne、Ballerini、Balitrand、Daniel、Fenaux、Castaigne和Degos等用APL病人的白细胞在体外做的实验表明，全反型维甲酸诱导白细胞分化所需剂量是13顺维甲酸的十分之一。因此，法国医生认为应该全反型维甲酸，而非13顺维甲酸。

国内对全反型维甲酸的疗效也多次验证。如，1991年，苏州医学院的Chen Zi-Xing等验证全反型维甲酸对APL的治疗作用。

1991年，美国纽约Sloan-Kettering癌症研究中心的Warrell等在中国王振义课题组1988年文章和法国Castaigne等（1990）年文章的基础上，用全反型维甲酸、但制剂稍改成美国常用胶囊，治疗了11例APL，9例完全缓解。Warrell等的工作发表于《新英格兰医学杂志》，有助于全反型维甲酸在美国推广。其后国际上很多验证全反型维甲酸作用的工作。

至此，国内和国际皆公认可以用全反型维甲酸治疗APL。

1994年，王振义当选中国工程院院士。同年，王振义与法国的Degos共享美国通用汽车癌症基金会Charles Kettering奖。1997年王振义获瑞士，1998王振义获法国奖项。也就是说，国际国内对王振义的认可皆基于其证明全反型维甲酸的治疗作用，而非以后以陈竺、陈赛娟为主，而王振义也以非通讯作者的身份加入过的机理研究。所以，张亭栋的工作最可比的是王振义的工作。

1997年，美国西北大学的Tallman与合作者在346位APL病人中比较全反型维甲酸和原有化疗（柔红霉素加阿糖胞苷），发现诱导和维持都用全反型维甲酸的疗效高于原有化疗、也高于维甲酸诱导后用原有化疗，得出清晰的结论：全反型维甲酸应该成为APL的治疗方法。Tallman等（1997）的文章发表于《新英格兰医学杂志》，使全世界医生认识到全反型维甲酸优于当时通用的APL化疗药物。

1990年代中期以后工作显示，全反型维甲酸和三氧化二砷可以分别应用、也可以联合治疗，进一步提高APL治疗成功率。这些工作中上海血液研究所陈赛娟、陈竺和王振义带领的梯队有很多贡献。

对于APL的分子机理，1977年，芝加哥大学著名细胞遗传学家Janet Rowley等发现APL患者细胞中发生了15号染色体和17号染色体移位（translocation）。1984年，与Rowley一道工作的Richard Larson等发现，27位APL的患者都有同样的15号染色体和17号染色体交换融合，融合位点全部在15q22和17q21.1。1990年，美国的Borrow等）和法国的de The等分别发现这一融合的分子结局：RARa（维甲酸a受体）的基因与另外一个基因PML融合，可以产生融合蛋白RARa-PML和PML-RARa。1991年，意大利的Alcalay等得到同样结论。RARa已知为受维甲酸调节的转录因子，而PML是含锌指区域的转录因子，这些突破奠定了APL分子机理的研究。后续研究表明，RARa-PML融合蛋白和PML-RARa融合蛋白调节基因转录，不同于正常RARa蛋白和PML蛋白。虽然15号与17号染色体互换融合产生PML-RARa融合蛋白是APL的主要发病原因，还有1-2%的APL致病是因为11号与17号染色体移位，这一移位的细胞遗传学发现为Najfeld等（1989）报道，其分子机理为1993年陈竺和陈赛娟两篇文章所报道。陈竺、Brand、Chen、陈赛娟、Tong、王振义、Waxman、Zelent在《欧洲分子生物学组织杂志》报道一例中国患者的11号与17号染色体移位导致RARa与另外一个锌指蛋白的基因PLZF融合。陈赛娟、Zelent、Tong、Yu、王振义、Derre、Berger、Waxman、陈竺在《临床研究杂志》发表论文发现一例中国患者APL患者11号与17号染色体移位导致RARa与PLZF基因融合。1994年，陈竺等报道PLZF-RARa融合蛋白可以抑制正常RARa的功能。也就是说，在王振义获得国内、国外认可的关键1994年以前，APL的机理研究以国外为主，而全反型维甲酸治疗APL的机理研究还很少。1994年后陈赛娟、陈竺还有很多对维甲酸治疗机理的研究，1990年代中期以后，陈竺、陈赛娟及王振义课题组起初与哈尔滨医科大学附属第一医院合作研究三氧化二砷的治疗作用，以后陈竺、陈赛娟及王振义对维甲酸和三氧化二砷治疗APL的机理还有很多研究，但都在1994年以后。从90年代至今，药物作用的分子机理方面的工作基本无王振义为主要作者（第一、或者通讯作者）的论文，而以陈竺和陈赛娟课题组为主。

本文讨论的张亭栋工作，最合适的比较是王振义的工作。因为两者都是发现或证明单体化合物的治疗作用，而且是对同一个疾病，所以最可比。王振义在1994年获得国内和国际认可原因是他证明全反型维甲酸对APL患者的治疗作用，与张亭栋的工作性质相似。不过张亭栋在1970年代的论文迄今未被英文文献所引用，所以国际上忽视了那些文章；而由于没有良好的风气，评价体系注重利益而缺乏自尊等多种原因，国内埋没了张亭栋的工作。

直到今天，张亭栋的三氧化二砷与王振义的全反型维甲酸两项工作，仍然是中国医药界突出的工作。

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