Papers by Dr. Tingdong Zhang and colleagues on the treatment of acute promyelocytic leukemia (APL) by arsenic trioxide

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, these 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。

 

1

Zhang TD, Zhang PF, Wang SR, and Han TY (1973). Preliminary clinical observations of 6 cases of leukemia treated by “Ailin solution”. Med Pharm Heilongjiang 1973(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 component among the several starting materials 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治疗作用的有效成分。

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。

 

2

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 Univ 1974(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。

 

3

Rong FX and Zhang TD (1979). A report on long term survival of 2 cases of acute granulocytic leukemia. J New Med Pharm 1979(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。

4

Zhang TD and Rong FX (1979). Treatment of acute granulocytic leukemia by Ailin No.1 and dialectic theory. Medicine and Pharmacy of Heilongjiang 1979(4):7-11 (张亭栋和荣福祥(1979).癌灵一号注射液与辩证论治治疗急性粒细胞型白血病. 黑龙江医药 1979(4):7-11).

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。

5 

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 Heilongjiang 1981(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 was a related report in 1982, in which Zhang and Li gave a talk 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”。

 

6 

Zhang TD (1982). Comments on questions about designing clinical research with combined Chinese and Western medicine. J Integrat Trad Chin West Med 2:180-181 (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.

 

7 

Zhang TD (1983). Understanding and treatment of leukemia by Chinese Medicine. J Trad Chin Med 1983(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. 

 

8 

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 therapeutic effect on M3 type were particularly obvious.

 

9 

Zhang TD (1985). Diagnosis and treatment of acute non-lymphatic leukemia. J Integrat Trad Chin West Med 5:713 (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-lymphatic acute leukemia. 

 

10 

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 Pharm 1991(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。

 

11 

 

Sun HD Ma L Hu XC Zhang TD (1992). Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integrat Chin & West Med 12:170-172 (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）。

 

12

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。

 

13

Li YS, Zhang TD, Wang XR, Liu X (1988). Investigation of the dynamics of Ailin No. 1 on human liver cancer cells. Research on Cancer Prevention and Treatment. 15:1-3 (李元善,张亭栋,王兴榕,刘旭(1988). 癌灵1号注射液对人肝癌细胞杀伤动力学研究. 肿瘤防治研究 15:1-3).

 

14

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 Surg 43:33-36.(三氧化二砷治疗肝细胞肝癌及其机理研究. 中华外科杂志）

PDF：2005 三氧化二砷对原发性肝癌的作用及其机理研究.pdf

 

15

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 Dig 14:207-209.（三氧化二砷治疗结肠癌现状 中西医结合杂志）

PDF：2006 三氧化二砷对结肠癌作用的研究近况.pdf