張亭棟、王振義與白血病的藥物治療
9月6日，2020年未來科學大獎揭曉，“生命科學獎” 頒發(fā)給哈爾濱醫(yī)科大學第一附屬醫(yī)院教授張亭棟和上海交通大學瑞金醫(yī)院教授王振義，以表彰“他們發(fā)現三氧化二砷和全反式維甲酸對急性早期幼粒細胞白血病的治療作用”。2011年北京大學饒毅、黎潤紅和張大慶的《中藥的科學研究豐碑》一文前半部分介紹屠呦呦的工作，后半部分——“三氧化二砷與張亭棟”。2013年，他們更新擴充的文章刊于《中國科學》雜志，以“化毒為藥：三氧化二砷對急性早幼粒白血病治療作用的發(fā)現”為題，其中不僅介紹了張亭棟的工作、也介紹了王振義的工作。《賽先生》轉載如下。
撰文 | 饒毅 黎潤紅 張大慶
摘要
在三氧化二砷（arsenic trioxide，ATO）被視為“對急性早幼粒白血病（APL）病人最為有效的單體”（Sanz et al., 2009; Tallman and Altman, 2009）的情況下，令人驚訝的是：最重要的發(fā)現者鮮為人知、其原始論文迄今未被一篇英文研究論文所引用。該發(fā)現產生于文化大革命時期，當時大多數中國科學家和醫(yī)生處于國家領導錯誤造成的困難時期。始于鄉(xiāng)村中醫(yī)針對性含糊的復方，張亭棟與同事于1970年代提出復方中單一的化學分子起作用、其最敏感對象為APL（張亭棟等，1973；張亭棟和榮福祥，1979）。張亭棟和同事二十多年的工作掃除了“能否”和“如何”有效使用ATO的困惑。此后中國和西方的其他研究者跟隨張亭棟等的先驅工作。張亭棟小組回顧性分析自己的資料證明APL確實為ATO最敏感的對象（張亭棟和李元善，1984；孫鴻德等，1991）。張亭棟所在醫(yī)院另一研究組將原本微量的氯化亞汞從配方中完全去除證明ATO單獨可以治療APL（張鵬等，1996）。1998年西方研究者發(fā)表重復和證明中國發(fā)現的論文導致ATO療法被廣泛接受（Soignet et al., 1998）。不過， ATO相關英文論文的西方或中國作者皆未引用張亭棟等1970年代的文章。本文集中介紹張亭棟等早期文獻，但也提示進一步研究和驗證中國報道ATO對其他腫瘤的作用，認為中國刊物發(fā)表的一些發(fā)現可能對病人有相當價值、其他國家的醫(yī)生可能得益于有最大病人群落的中國醫(yī)生之臨床經驗。
本文關鍵詞：白血??；砒霜；三氧化二砷；張亭棟
急性早幼粒白血病（APL）曾為急性白血病中發(fā)病最兇險和后果最致命之一，而現在是最能被治療的白血病之一。雖然對APL的治療還有可改進之處，過去幾十年來其治療有很顯著的改善，因為使用了阿糖胞苷（cytarabine， arabinosyl cytosine, Ara-C) (Ellison et al., 1968)，蒽環(huán)類抗生素（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)，和全反型維甲酸（all-trans retinoic acid，ATRA）(Huang et al., 1987, 1988)。
阿糖胞苷、蒽環(huán)類抗生素（如柔紅霉素，daunorubin）和維甲酸的發(fā)現廣為人知，而ATO療法的發(fā)現史鮮為人知：多數APL研究者引用1990年代的論文，晚于原創(chuàng)論文近二十年；有些作者不清楚ATO最初發(fā)現者。這些錯誤令人遺憾，特別是考慮到歐洲白血病國際專家委員會已認為ATO是“APL療法中最具生物學活性的單體”（Sanz et al., 2009）、也被認為是“APL病人最有活性的單體” （Tallman and Altman, 2009)，而ATO與ATRA合并用藥可能“在不久的將來，在多數、如果不是全部病人中，替代傳統(tǒng)療法”（Tallman and Altman, 2009）。過去十余年來見證了ATO的普遍接受（Sanz and Lo-Coco, 2011）、愈來愈多的證明ATO在初發(fā)和復發(fā)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獻發(fā)表于中國人也少讀的中文期刊，但還有其他更復雜的因素。本文總結早期文獻，從發(fā)現ATO治療白血病到普遍接受ATO治療APL。我們也提供早期中文文獻的英文翻譯，以便西方作者引用。
本文作者并非白血病的研究者，而是以科學史研究者的身份寫此文。我們希望白血病的研究者和醫(yī)生更為仔細地閱讀原始文獻。
ATO發(fā)現的文化環(huán)境和非典型歷史
1960年代中期至1970年代中期，中國處于稱為“偉大的文化大革命”的政治動蕩期。雖然它源于當時中國最高領導毛澤東的政治意圖，文革直接和間接影響了多于一代的中國人。有觀點認為今天中國發(fā)生的部分乃文革的后果或對文革的反應，多數認為文革是負面的，如果不是災害性的。
文革很多極左政策，多數是有害的，但有些有混合、甚至正面的作用，這些正面作用有些源于政策制定者的意圖、有些并非原意。與毛直接有關的一個政策是改善農村醫(yī)療條件，從城市醫(yī)院派遣“流動醫(yī)療隊”到鄉(xiāng)村服務，醫(yī)療隊走訪多個村莊、醫(yī)療隊成員輪換。另一政策是強調中國傳統(tǒng)醫(yī)藥。這兩項政策的交匯導致當時很多“發(fā)現”中醫(yī)藥有很強療效的聲稱，這些聲稱多數在幾年內被遺棄。但是，少數經受了時間的考驗。ATO的發(fā)現是這種例子。
砷曾長期為中外使用。多種傳統(tǒng)中藥配方含砷，但通常含多種化學分子、針對的疾病不非常清晰。西方使用砷也不確定（Sears, 1988）。例如，1786年英國的Thomas Fowler 發(fā)明含砷化鉀（KAsO2）的溶液，將其用于瘧疾、間歇熱、周期性頭痛等（Sears, 1988）。1845年發(fā)現白血病后，Fowler氏液于1865年被用于治療白血病，并于1931年再度用于白血病 （Jolliffe, 1993）。其后砷和放射作為治療慢性髓細胞白血病（chronic myelocytic leukemia， CML）的主要療法，直至1953年被馬利蘭（busulfan）化療所替代（Sears, 1988; Jolliffe, 1993），不再是西方治療白血病的常規(guī)藥物。
1958年，中國哈爾濱醫(yī)科大學的關繼仁試用Fowler液治療白血病，結論是砷劑無效（Guan, 1958）。1950和1960年代，北京的周靄祥和上海的顧德謦使用含硫化砷的中藥復方治療白血病（Gu, 1964）。1972年，一個標明“內部資料”的刊物“遼寧抗癌戰(zhàn)訊”發(fā)表朝陽人民醫(yī)院兒科的文章，報道用砷劑和化療合并治療16例兒童急性粒細胞白血病。這一治療沒分開砷劑和其他化療，不清楚砷劑是否有超出化療已有作用的效果，也不知道有多大效果：16例的成功率未報道、僅分析了一例的血象。
1974年中醫(yī)研究院血液組總結了全國當時已經試過的、基于中醫(yī)藥的途徑和藥物，它列了硫化砷（As2S3）和蟾酥（以及其他，包括完全西方發(fā)明的藥物）（Hematology Group, 1974）。它將關繼仁（1964）和朝陽人民醫(yī)院（1972）作為支持As2S3療效的兩篇文獻。需要指出，顧德謦和周靄祥并未將他們的復方化解為單方，即使到今天（如，Zhou，1998；Huet al., 2011）。因為含As2S3 的中藥制備過程并無導致As2S3氧化為ATO的高溫，在這些砷劑中As2S3與ATO的關系不明。1974年的綜述無結論性地建議用哪種中藥治療白血病。該文所討論治療白血病的蟾酥和多種其他中藥其后并未成為任何亞型白血病的標準療法。
總之，至1974年，并無定論用什么中藥治療白血病、已試過的中藥的有效性也不確定。
1970年代初，哈爾濱醫(yī)科大學附屬第一醫(yī)院藥劑科的韓太云參加巡回醫(yī)療隊，得知鄉(xiāng)村中醫(yī)用含砷、汞和蟾毒等的復方治療淋巴結核和多種。1973年3月，韓太云將這三者做成注射液，他按年月命名為“713”溶液、亦稱“癌靈”。肌肉注射“713”對有些癌癥病人有效，一時風靡當地，但又因其毒性很快消停?！?13”針對的疾病并不清晰，其有效成分也未確定。
張亭棟與韓太云同在一個醫(yī)院。張亭棟出生于1932年，1950年代早期學習西醫(yī)后畢業(yè)于哈爾濱醫(yī)科大學，1960年代曾進修中醫(yī)，長期工作于哈爾濱醫(yī)科大學附屬第一醫(yī)院中醫(yī)科。最初他被黑龍江省衛(wèi)生局派去檢查鄉(xiāng)村中醫(yī)所言是否屬實，其后張亭棟與韓太云合作。
ATO治療APL的原始發(fā)現: 1973至1979
1972年后，張亭棟與同事將研究集中于白血病。他們也思考了713的成分，提出砷是唯一的治療性化學分子，而汞與蟾酥汞無治療白血病的作用，汞導致腎毒性、蟾酥導致高血壓等副作用。從此，他們用的“癌靈1號”主要含ATO、僅微量汞（ATO與氯化亞汞的重量比為100：1），而全無蟾酥。
1973年，張亭棟與韓太云的第一篇文章發(fā)表于當地的中文刊物。張亭棟、張鵬飛、王守仁、韓太云報道“癌靈”治療6例慢性粒細胞白血病（Zhang et al
., 1973）。他們明確陳述所用溶液含ATO和微量氯化亞汞，所有6位病人都在治療后有改善，他們提到還在治療急性白血病，但該文中未發(fā)表其結果。
1974年，哈爾濱醫(yī)科大學第一附屬醫(yī)院中醫(yī)科和血液科為集體作者在該校的校報發(fā)表文章（Departments, 1974），總結1973年1月至1974年4月治療的17例白血病人。在觀察不同類型白血病后，他們報道癌靈1號可以治療多種白血病，有些可以達到完全緩解（complete remission，CR）。1976年，他們以集體作者還發(fā)表了5例急性白血病的治療，皆CR。
1979年，榮福祥和張亭棟報道兩例急性粒細胞白血病，一例CR已4年、一例3年（Rong and Zhang, 1979）。
1979年，張亭棟和榮福祥發(fā)表當年的第二篇文章，總結他們治療55例急性白血病（Zhang and Rong, 1979）。其中，23例從1973年至1974年僅用癌靈1號，20例從1975年至1976年用癌靈1號加西醫(yī)化療及其他中藥，12例從1977年至1978年用癌靈1號加中藥和化療。對每個病人，他們顯示了白血病的亞型和臨床觀察。所有55例都有一定程度的改善，總緩解率為70%，而12例為CR。他們用的劑量副作用較小。他們以相當于成人劑量十倍的劑量注射到家兔，病理解剖后沒有見心、肝、脾、腎的毒性。
1973年文章報道了他們先驅的發(fā)現，1979年的第二篇文章代表他們對療效的理解（Zhang and Rong, 1979）。張等早期工作有三個重要問題：1）他們是否證明治療作用來源于癌靈一號，而不是其他中藥或化療西藥？2) 他們是否意識到癌靈1號的作用來源于ATO而不是溶液中的汞？3）他們是否知道ATO對APL的作用？
以上三個問題的答案都可在Zhang and Rong (1979) 一文看到：1）三例患者（一例成人、兩例兒童）只用了癌靈1號，未用其他任何西藥和中藥，療效顯著。論文發(fā)表時，兒童存活4年多、成人逾9給月。當使用其他中藥時，他們指出不是治療白血病，而是支持患者健康狀態(tài)以便接受治療；2）他們文章第11頁提出癌靈1號的有效成分是ATO；3）他們在文章的第10和11頁反復指出ATO最敏感的白血病是法國-美國-英國FAB分型的M3型（另一名稱為APL ）。
我們可以看到，至1979年，張亭棟和同事的理解與現在相同：ATO可以治療白血病，特別是M3型（亦稱APL）的白血病。
張亭棟研究組1980至1990年代的進一步工作
1981年，以集體作者（但標明張亭棟為指導，含8位其他作者）的文章報道，癌靈1號使73位急性粒細胞白血病人中24%的CR、總緩解率86%（Department, 1981）。1982年，張亭棟和李元善在全國會議上報道癌靈1號治療后CR的22例、以及治療98例非淋巴細胞白血病，張在1982和1983年總結其工作（Zhang, 1982, 1983)。
1984年，張亭棟和李元善總結他們自1971年以來治療的81例患者（Zhang and Li，1984）。在CR的22例中，他們指出7例為M2型、15例為M3型。他們再次認為“以M3型效果尤為顯著”。張亭棟另發(fā)文章有關癌靈1號對非淋巴細胞型白血病的作用（Zhang，1985）。
1991年，孫鴻德、馬玲、胡曉晨、張亭棟、榮福祥、王欽華、李金梅、馮秀芹 (Sun
1992年，孫鴻德、馬玲、胡曉晨、張亭棟（Sun et al., 1992）以短篇“經驗交流”綜述了與他們1991年文章完全相同的實質內容。奇怪的是，多數英文文章都引用1992年這篇文章作為發(fā)現ATO治療APL，雖然這兩篇文章皆中文。
因為張亭棟從1973至1992年的文章所報道的治療都含微量氯化亞汞，雖然遠低于ATO（重量比1:100），嚴格地說，他們未證明氯化亞汞毫無益處，雖然他們在1973年的文章中就說過癌靈1號的有效成分是ATO。
1995和1996年，張亭棟同一醫(yī)院的張鵬、王樹葉、胡龍虎、施福東、邱鳳琴、洪珞珈、韓雪英、楊惠芬、宋穎昭、劉艷平、周晉、金鎮(zhèn)敬等發(fā)表兩篇論文，證明沒有汞的情況下，僅有ATO也完全有療效（Zhang et al., 1995, 1996）。1995文章為摘要，沒有明確所用的“713”注射液不含汞，不過后來張鵬說明他們只用了ATO（Zhang，2013）。1996年文章明確只有ATO、無氯化亞汞。他們從1992年至1995年治療了130位患者，其中72例一次或多次治療。他們治療初發(fā)病人的CR可達73%，在復發(fā)再治病人的CR可達52%（Zhang et al., 1996）。
在發(fā)掘ATO研究的過程中，我們沒有看到跡象證明傳統(tǒng)中醫(yī)理論對疾病的分型對發(fā)現ATO的靶疾病有用。在此，我們將傳統(tǒng)中國醫(yī)藥分成中醫(yī)理論（CMT）和中藥。CMT對發(fā)現ATO治療白血病重要嗎？張亭棟等討論了依據CMT對白血病分五類，但ATO對這些類型作用無差別（Rong and Zhang, 1979; Zhang and Rong, 1979; Departments, 1984）。而西醫(yī)對白血病的分型有助于發(fā)現ATO的靶疾病。當他們完全放棄CMT對白血病的分型時，ATO對靶疾病的作用更為顯著。有趣的是，他們1973年第一篇文章并未用CMT，而后來的文章提到。缺乏支持CMT用處的證據并不能證明CMT無用，但迄今不明確CMT是否對于傳統(tǒng)中藥的研究是否重要。
中國對APL治療的貢獻
阿糖胞苷和蒽類抗生素（包括柔紅霉素）等因為西方的研究成為APL的一線藥物（Ellison et al., 1968; Boiron et al., 1969; Bernard et al., 1973）。此后，中國因為ATO和ATRA的發(fā)現而有顯著改善APL的治療。本文將中國的發(fā)現放在當時的歷史框架中。
1973年，中國的張亭棟和同事報道ATO對白血病的治療（Zhang et al., 1973）。1979年張亭棟和榮福祥提出APL對ATO特別敏感（Zhang and Rong，1979）。
1977年，美國癌癥研究所的Collins等成功地從APL病人來源的細胞建立了細胞系（HL-60）（Collins, Gallo and Gallagher，1977）。1978年，Collins等用此細胞系篩選藥物，找可誘導 HL-60細胞分化成熟為正常細胞的化合物。1980年，Brietman, Selonick and Collins 發(fā)現全反型維甲酸（ATRA）和13順型維甲酸可以誘導HL-60分化為成熟的細胞，相關的化合物如維生素A作用低一千倍。他們提出“這一化合物可以提供治療急性髓細胞白血病的新治療工具”。
1981年，Breitman、Collins 和Keene從白血病患者血中獲得白細胞，檢測它們對藥物的敏感性，發(fā)現ATRA能夠誘導分化的細胞皆來自兩位APL患者。1982年，Olsson和Brietman 發(fā)現維甲酸也能誘導U-937淋巴瘤細胞分化。1983年，日本的Honma等報道多種化合物可以誘導不同白血病人的細胞分化，發(fā)現ATRA可以誘導APL患者白細胞的分化。美國的Koeffler (1983) 總結了體外結果，包括用維甲酸和其他化合物誘導細胞分化，認為ATRA和13順維甲酸對APL白細胞有同等的分化誘導作用。
美國和歐洲的四個研究組分別報道了13順維甲酸成功地治療APL個例：美國明尼蘇達的 Flynn 等 (1983)；瑞典Lund的Nilsson (1984)；荷蘭的Daenen等 (1986) ；以及美國西佛吉尼亞的Fontana, Roger and Durham (1986)。
1985年，上海第二醫(yī)學院的王振義在當地能獲得ATRA，但不能獲得13順維甲酸，他用ATRA成功地治療了一例5歲APL女孩。1987年，他的研究組在《中華醫(yī)學雜志》發(fā)表英文論文，報道單用ATRA、或ATRA合并其他化療治6例APL患者（Huang et al., 1987）。1988年，王振義研究組在國際的《血液》雜志發(fā)表他們用ATRA治療24例APL（Huang et al., 1988）。該文引用了1980年Breitman、Selonick,、Collins的文章，1981年Brietman,、Collins、 Keene 的文章，以及1983年Koeffler報道ATRA和13順維甲酸誘導白細胞分化的文章，也引用了1983年Flynn et al.、1984年Nilsson、1986年Daenen et al.及Fontana et al. 等報道13順維甲酸治療APL的多篇文章。
Huang et al. 在1988和1987年的兩篇都是英文論文，但1988年的文章在美國發(fā)表、1987年的文章在中國發(fā)表，前者獲國際關注。與法國醫(yī)生的直接交流也有助于國際關注。王振義研究組ATRA的發(fā)現很快被重復。1989年，法國的Chomienne等將ATRA和13順維甲酸分別給兩例APL患者，比較兩個藥物的療效，感覺ATRA更有效。1990年，同一法國研究組在體外研究了來自于22例APL患者的白細胞，認為ATRA的作用是13順維甲酸的十倍（Castaigne et al., 1990）。ATRA的作用也被中國其他醫(yī)生驗證（如，Chen ZX et al., 1991）。1991年，美國的Warrell等驗證了中國王振義組和法國Degos組的療效，成功地治療了11例APL中的9例。自此，ATRA治療APL 廣為人知。1997年，Tallman等報道用346例APL比較ATRA和此前標準化療的柔紅霉素和阿糖胞苷，發(fā)現如果ATRA在誘導和維持期都用時療效高于化療。
1992年，段秀綿、辛曉敏、王鳳芹、馮秀芹、徐敬肅、宋曉時、張月桂報道ATO體外對白細胞的作用。1995年，大連的黃世林、郭愛霞、向陽、王曉波、林慧嫻、富麗報道復方青黛片在65位APL患者中獲 98%的CR，他們用藥成分中含硫化砷。
1995年和1996年2月，哈爾濱的張鵬、王樹葉、胡龍虎、施福東、邱鳳芹、洪珞珈、韓雪英、楊惠芬、宋穎昭、劉艷平、周晉、金鎮(zhèn)敬報道從1992年至1995年在130位APL中單用ATO獲得73%的CR。ATO與ATRA之間無交叉耐受（Zhang et al., 1995, 1996）。
1996年8月，上海第二醫(yī)學院血液研究所的陳國強等19位作者（包括中間作者張亭棟、最后作者陳賽娟、王振義、陳竺）報道用體外培養(yǎng)的白血病細胞在分子水平研究ATO的治療機理（Chen et al., 1996）。
1997年, 徐敬肅、段秀綿、徐瑩、辛曉敏、宋曉紅、張亭棟報道一例三度發(fā)病的APL患者，每次用癌靈1號治療后存活了二十多年（Xu et al., 1997）。
1997年，上海血液所的陳國強等報道ATO體外作用于白血病細胞的良效關系。1997年，上海上海血液所的的沈等報道15例APL患者的治療，其中10例單用ATO，CR達90%。
1998年，美國Sloan-Kettering癌癥研究中心和康奈爾醫(yī)學院的Soignet 等在《新英格蘭醫(yī)學雜志》報道他們用ATO治療12例復發(fā)的APL患者，11例CR（Soignet et al.，1998）。
Soignet 等的1998年論文很有利于國際接受ATO作為APL的治療方式，這是中國醫(yī)生此前二十多年在國內發(fā)表的很多文章未能做到的。
缺乏認可
現在，國際和國內都很接受和使用ATO，救活了中外患者。但是，發(fā)現者基本在學術和醫(yī)療社群默默無聞，盡管2001年曾有《紐約時報》的報道 （Rosenthal, 2001）。更為鮮明對照的是， 雖然ATRA治療APL導致王振義獲得多個國內外榮譽，張亭棟或他的哈爾濱同事沒有因為ATO治療APL而獲一個全國性或國際性獎勵。而我們知道，ATO的發(fā)現早ATRA十余年，且為歐洲白血病專家委員會認為是“APL最具生物學活性的化合物”（Sanz et al., 2009）。
缺乏認可并非因為爭議。張亭棟研究組的孫鴻德曾提出專利爭議，但提出時間較晚，而且法院判案支持張亭棟。張鵬堅持他第一證明ATO無需汞可以單獨治療APL。確實，1979年張亭棟和榮福祥曾提出ATO單獨有作用，但他們沒有顯示單獨用ATO的資料。孫鴻德和張鵬有重要貢獻，但很清楚張亭棟的作用毫無疑問最為關鍵，他從1970年代初到1990年代初堅持不懈的工作，改觀了人們對砷之用處和效果的想法：以前砷無確切的用法、療效不定，他的工作后砷的使用實際可行、且療效顯著。
1998年，陳國強、陳賽娟、王振義、陳竺在中文雜志表示：自1970年代初，哈爾濱醫(yī)科大學通過臨床實踐發(fā)現三氧化二砷可以有效地治療APL，近兩年來，我們與哈醫(yī)大合作，用三氧化二砷溶液治療對全反維甲酸和化療耐藥的APL患者（Chen et al., 1998）。這類陳述肯定了哈爾濱工作的優(yōu)先，不過這篇綜述文章中沒有出現張亭棟的名字、也未引用其1970年代的文獻。
幾乎沒有英文論文意識到張亭棟在1973至1979年已發(fā)表過論文。英文論文，即使是中國學者的英文論文，也僅引1992年孫鴻德等（Sun et al.， 1992)、有時引用 1996年張鵬等的論文（Zhang et al.，1996），視它們?yōu)锳TO治療白血病的最早論文。例如，1998年Soignet等文章重復張亭棟1970年代論文、并對國際接受ATO起了很大作用，但它稱“中國最近報道”ATO治療APL導致CR，引用的是1992年孫鴻德（Sun et al.，1992)、1996年張鵬等（Zhang et al.，1996)、1997年上海血液所的沈等（Shen et al.，1997)。從1998年Soignet 等論文不可能知道張亭棟在1970年代就有原創(chuàng)的發(fā)現，因為文章的基調和引用讓讀者認為中國的發(fā)現是在1990年代。
美國的《科學》雜志在1996年一篇新聞報道曾提到張亭棟（Mervis, 1996），但卻稱張亭棟于1992年發(fā)表論文。
張亭棟本人很少發(fā)表英文論文。2001年，他與陳國強作為共同第一作者、王振義和陳賽娟作為中間作者、陳竺作為通訊作者在國際雜志《癌基因》發(fā)表綜述（Zhang et al., 2001）。在引言部分，他們說“最近”研究ATO治療APL，引用的是1996年上海血液所等陳國強等（Chen et al.，1996)。第二頁，他們說ATO的研究始于1971年，但未引用任何文獻；也說他們治療了包括慢性粒細胞白血病、淋巴瘤、食管癌以及特別是APL等多種癌癥、上千患者，但還是沒引文獻。如此，張亭棟看起來作為第一作者的英文論文也沒引用他自己早年的文獻，有效地埋葬了1970年代的先驅工作。
2002年，朱軍、陳竺、Lallemand-Breitenbach和de The在《自然綜述 癌癥》發(fā)表綜述文章。在描繪APL治療里程碑的圖中有張亭棟在1970年的工作，但文字部分引用還是1992年孫鴻德等（Sun et al.，1992)，在參考文獻中稱1992年孫鴻德等的文章為“第一篇三氧化二砷治療APL的報道”。
1991年孫鴻德等和1996年張鵬等皆為中文論文，卻都未引用1970年代的文獻。所以，如果有國際學者希望通過有人幫助他們翻譯1992和1996的文章，他們也不可能由此知道1970年代的原始文章。
2008年，王振義和陳竺在《血液》發(fā)表APL治療進展的綜述，其對ATO引用的第一篇是2002年朱軍等（Zhu et al.，2002)，后面還引了1992年孫鴻德等、1996年張鵬等，以及上海血液所三篇文章（1996年陳國強等、1997年沈等、1999年牛等)。
2011年，陳賽娟和陳竺等五位作者發(fā)表ATO治療APL的綜述（Chen et al.，2011），稱“1970年代早期，中國東北哈爾濱醫(yī)科大學一個小組檢測了含1%ATO和微量氯化亞汞的癌靈1號在靜脈注射后對多種癌癥的作用”，但未說明研究者、也未引用1970年代的文獻。它引用1992年孫鴻德等作為“癌靈1號在32位患者中21位CR，并有30%的令人印象深刻的十年存活率”，然后說“單獨用ATO治療復發(fā)的APL是上海血液研究所自1996年至1999年報道的”，引用上海的文章是1997年沈等和1999年牛等, 忽略哈爾濱張鵬等1995和1996年的兩篇文章，其中1996年張鵬等說明了只用ATO、無氯化亞汞。按照張鵬于2013年的博客文章，張鵬等的結果于1995年在全國會議上宣讀，陳竺等出席會議者應該知道（Zhang, 2013）。但按2011年陳賽娟和陳竺等在國際刊物的綜述，首先報道單獨用ATO治療APL不是1996年的張鵬等、而是上海血液所在1997和1999的文章。
2011年香港一篇文章，跟蹤ATO治療APL十年的療效，但它只引用美國作者2001年的文章（Au et al.，2011），連內地作者1990年代的文章也不引。
這樣，本來應該可以讀中文的作者無一在發(fā)表英文論文時引用了1970年代的文章。在當今英文作者連法文和德文也不讀的情況下，毫不奇怪他們不知道中文的原始文獻。張亭棟的貢獻、他發(fā)現的準確時間因此而不為國際學術和醫(yī)療界所知。
注意中文發(fā)表的工作之意義
過去，一般傾向于忽視中國的臨床研究，語言只是部分理由。有大量病人的中國，其醫(yī)生常常有多于西方醫(yī)生的臨床經驗。有些中國醫(yī)生，即使是少部分中國醫(yī)生，可能對治療有洞見，但只發(fā)表在中國刊物。
以ATO為例，包括張亭棟在內的中國醫(yī)生報道了ATO治療多種癌癥，從肝癌、胃癌、結腸癌到淋巴瘤（Li et al., 1988; Liu et al., 2005; Guo et al., 2006）。這些似乎值得驗證。
間接推斷中藥成分的嚴格科學研究還可能有更多發(fā)現。例如，一些醫(yī)院自己試用的藥物、和一些中藥企業(yè)缺乏嚴格測試就猛力推進市場的藥物。而可能在嚴格檢驗和研究后，會更為有效和有針對性，而更獲得國際接受，最終幫助更多病人，挽救更多生命。
（上文為饒毅，黎潤紅，張大慶《化毒為藥：三氧化二砷對急性早幼粒白血病治療作用的發(fā)現》，2013年發(fā)表于《中國科學 生命科學》 43:700-707，英文發(fā)表于2013年《中國科學 生命科學》Science China Life Sciences 56:1-8。英文版原文見下。）
A drug from poison: how the therapeutic effect of arsenic trioxide (ATO) on acute promyelocytic leukemia (APL) was discovered
Yi Rao, Runhong Li and Daqing Zhang
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)(Huang et 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
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 As2S3 and 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 As2S3 did 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.
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.
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.
Chinese Contributions to APL Treatment
Anthracyclines (including daunorubin) and cytarabine became frontline treatment for APL because 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.
Huang et 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.
Duan et 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.
Chen et 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%.
Soignet et 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 NEJM paper 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.
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 Sun et al. (1992), Peng Zhang et al. (1996), and Shen et al. (1997). It is impossible to know from the NEJM paper 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 Science did 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 As2O3 therapy 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, and further 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 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.
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.
致謝：作者之一（YR）感謝中醫(yī)研究院李連達告知兩篇文章（Guan 1958, and Chaoyang People’s Hospital, 1972），以及周靄祥和顧德馨的工作。
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