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

張亭棟等研究三氧化二砷治療急性早幼粒細胞白血病的部分論文

 

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.

早幼粒細胞白血病APL的治療有顯著改善， 歸功于Ellison等（1968）引入cytarabine， Boiron等（1969）引入daunorubicin， 張亭棟等（1973）引入三氧化二砷， 王振義課題組以黃等（1987）發表的論文引入全反型維甲酸 。

這些工作中最不為人所知的是張亭棟醫生和同事的先驅工作：沒有一篇英文論文引用他們在1970年代發表的有關三氧化二砷的重要原始論文。

為減輕這一問題，我在此列出張亭棟醫生和同事的部分文章，并提供PDF鏈接。我建議未來的有關文章引用張亭棟等（1973），張亭棟和榮福祥（1979）兩篇論文。

有據可查的文獻很清晰地顯示，張亭棟在這一工作中起了關鍵作用，不同的合作者對一些不同方面有貢獻，但只有張亭棟對該研究的整體、和每個關鍵步驟都有貢獻。

中國另有使用含雄黃的復方的工作，迄今未化解為單體化合物，并不清楚起作用的化學成分，迄今它們與三氧化二砷的關系仍然不明。因此，張亭棟與同事的工作也突出于這些工作，因為只有張亭棟等的工作從多種材料中定義了單個分子。

 以下為部分關鍵論文的引用信息，PDF文檔，和內容、背景簡介。

 

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 (張亭棟,張鵬飛,王守仁,韓太云(1973) “癌靈注射液”治療6例白血病初步臨床觀察.黑龍江醫藥 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.

張亭棟、張鵬飛、王守仁、韓太云在本文中報道他們用“癌靈注射液”（以后也稱“癌靈1號”）治療6例慢性粒細胞白血病病人。他們明確知道主要用了砒霜的化學成分“亞砷酸（三氧化二砷）”和微量“輕粉（氯化低汞）”。經過治療，6例病人癥狀都有改善，其中一例為慢性白血病發生急性變的患者也有效。該文還提到作者們還在研究對急性白血病的治療效果。

此前，哈爾濱醫科大學第一附屬醫院的藥師韓太云得知民間中醫用砒霜、輕粉（氯化亞汞）和蟾酥等治療淋巴結核和癌癥。1971年3月，韓太云將它們改制水針劑，稱"713"或"癌靈"注射液，通過肌肉注射，對某些腫瘤病例見效，曾在當地風行一時，但因毒性太大而放棄。韓當時沒有確定癌靈適用的特異疾病、亦未確定癌靈幾種成分中何為治療作用的有效成分。

張亭棟是同一醫院的醫生，黑龍江省衛生廳曾請他檢查農村中醫聲稱的醫療效果。1972年，張亭棟與韓太云合作。張亭棟等一方面主要集中做白細胞，而非無選擇地將藥物用于從結核到多種癌癥等很多疾病，另一方面，張亭棟等用血象分析等可靠的客觀標準檢測治療效果,而鄉村中醫無此標準。

 

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 (哈醫大一院中醫科，哈醫大一院檢驗科(1974). 癌靈1號注射液與辨證論治對17例白血病的療效觀察. 哈醫大學報 1974(2):25-30).

PDF:1974 癌靈1號注射液與辨證論治對17例白血病的療效觀察 哈醫大學報 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.

本文總結從1973年1月至1974年4月對不同類型白血病的治療效果，發現“癌靈1號”對多種白血病有效、對急性白血病可以達到完全緩解。

另外，沒有在此例出的一篇相關文章是：1976年哈醫大一院中醫科曾撰文“中西醫結合治療急性白血病完全緩解五例臨床紀實”，介紹5例經治療后完全緩解的患者的診治過程及各種臨床表現。

 

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 (榮福祥,張亭棟(1979). 急性粒細胞性白血病長期存活2例報告. 新醫藥學雜志 1979(6):31-34).

PDF:1979 Rong & Zhang 急性粒細胞性白血病長期存活2例報告.pdf

Summary:

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

       本文報道“癌靈1號”治療后存活4年半和3年的兩例病人，皆為急性粒細胞性白血病。

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 (張亭棟和榮福祥(1979).癌靈一號注射液與辯證論治治療急性粒細胞型白血病. 黑龍江醫藥 1979(4):7-11).

PDF:1979 Zhang & Rong 癌靈一號注射液與辨證論治治療急性粒細胞型白血病.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年張亭棟和榮福祥總結他們從1973年至1978年治療急性粒細胞型白血病共55例。其中1973年至1974年單用“癌靈一號”治療23例，1975年至1976年用“癌靈一號”加其他中藥和少量化療藥物治療20例，1977年至1978年用“癌靈一號”加其他中藥和加少量化療治12例。對每一個病例，他們都根據血象分型，有明確的療效觀察。全部55例都有不同程度的好轉，緩解率70%，12例完全緩解，對病人的毒副作用小。他們還用十倍于成人的劑量，給12只家兔注射“癌靈一號”，未見心、肝、脾、腎毒性作用。

張亭棟和榮福祥（1979）明確指出：1）有三例病人（一位成人、兩位兒童），單純使用“癌靈一號”，不用其他中藥、不用化療西藥，也顯示療效，其中當時兒童存活已經4年，成人已存活9個月。在使用其他中藥時，他們也指出其他中藥并非治療白血病、而用來支撐病人身體狀況；2）在第11頁，他們指出“癌靈一號”之有效成分為三氧化二砷；3）在第10頁和第11頁，他們兩次明確指出對早幼粒型白血病效果最好。也就是說，1973年到1979年，張亭棟與不同的同事合作發表的論文，清晰地得到了我們今天的認識：三氧化二砷可以治療白血病，特別是急性早幼粒白血�。ǚ▏�-美國-英國FAB分型的M3型白血病，也即acute promyelocytic leukemia，APL）。

1973年的論文是他們發現“癌靈一號”的開創性論文，開始將砒霜用于白血�。ǖ�當時只報道了慢性白血�。�，而張亭棟與榮福祥（1979）是他們這一系列工作的代表性論文。張亭棟與榮福祥（1979） 論文已經明確：1）癌靈一號只需要三氧化二砷起治療作用；2）最敏感的白血病是M3型的急性粒細胞白血�。ê髞硪卜Q為APL）。

有不同的合作者參與1973、1974、1979年發表的工作，而張亭棟自始至終參與，并作為主要作者，所以發表的文獻清晰地表明張亭棟的關鍵作用。

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 (哈爾濱醫科大學附屬第一醫院中醫科 （指導:張亭棟 執筆: 李元善 胡曉晨 參加人:李明祥 張鵬飛 榮福祥 孫洪德 李會榮 吳云霞 檢驗科血研究室）（1981）癌靈一號結合辨證施治治療急性粒細胞型白血病73例臨床小結. 黑龍江中醫藥 1981(4):28-30).

PDF:1981 癌靈一號結合辨證施治治療急性粒細胞型白血病73例臨床小結.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年哈爾濱醫科大學附屬第一醫院中醫科 （文章最后注腳標明 指導：張亭棟；執筆：李元善，胡曉晨；參加人：李明祥，張鵬飛，榮福祥，孫洪德，李會榮，吳云霞，檢驗科血研究室）報道“癌靈一號”對急性粒細胞白血病完全緩解率達24%、總緩解率達86%。

在此未列出來，另外在1982年的全國中西醫結合治療白血病座談會上，張亭棟、李元善交流了“癌靈1號治療急性粒細胞白血病臨床實驗研究—附22例完全緩解分析”和“98例非淋巴細胞白血病分型與臨床療效探討”。

 

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 (張亭棟 （1982） 談談中西醫結合臨床科研設計中的幾個問題. 中西醫結合雜志2:180-181).

PDF:1982 Zhang 談談中西醫結合臨床科研設計中的幾個問題.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 (張亭棟 （1983） 中醫對白血病的認識和治療. 中醫雜志 1983(3):71-74).

PDF:1983 Zhang 中醫對白血病的認識和治療.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 (張亭棟,李元善(1984). 癌靈1號治療急性粒細胞白血病臨床發現和實驗研究。 中西醫結合雜志4:19-20).

PDF:1984 Zhang & Li 癌靈1號治療急性粒細胞白血病臨床分析及實驗研究.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.
張亭棟和李元善(1984)總結他們1972年以來治療的81例急性粒細胞白血病，分析其中完全緩解的22例。他們指出，完全緩解的22例中，7例為M2型，15例為M3型白血病。他們也再次指出“以M3型效果尤為顯著”。

 

9

Zhang TD (1985). Diagnosis and treatment of acute non-lymphatic leukemia. J Integrat Trad Chin West Med 5:713 (張亭棟 （1985） 急性非淋巴細胞性白血病證治. 中西醫結合雜志 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 (孫鴻德,馬玲,胡曉晨,張亭棟,榮福祥,王欽華,李金梅,馮秀芹 (1991) 癌靈1號結合中醫辨證施治急性早幼粒白血病長期存活16例報告. 中醫藥信息 1991(6):39-41).

PDF:1991 Sun et al 癌靈1號結合中醫辨證施治急性早幼粒細胞白血病長期存活16例報告.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.

孫鴻德、馬玲、胡曉晨、張亭棟、榮福祥、王欽華、李金梅、馮秀芹發表“癌靈1號結合中醫辨證施治急性早幼粒白血病長期存活16例報告”，應該是延伸1984年張亭棟和李元善的文章。他們報道從1974年到1985年以“癌靈一號”治療急性早幼粒白血病32例，19例完全緩解，16例存活超過五年。

 

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 (孫鴻德,馬玲,胡曉晨,張亭棟 (1992).癌靈1號結合中醫辨證治療急性早幼粒白血病32例. 中國中西醫結合雜志 12:170-171).

PDF:1992 Sun et al 癌靈1號結合中醫辨證治療急性早幼粒細胞白血病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.

孫鴻德、馬玲、胡曉晨、張亭棟這篇作為“經驗交流”發表的短文，實質相同于1991年論文。比較奇怪的是，英文文獻引用這篇文章。該文與1991年論文一樣都是中文，內容不過是1991年論文的簡介，而實際發現最早發表于張亭棟等（1973），到張亭棟和榮福祥（1979）已明確了對APL的作用最好。而1992的論文在本質上與1979年的文章無差別，既沒有改變所用的藥物成分、也沒有改變適應癥。 沒有科學理由引用孫鴻德等（1992）而不引用張亭棟等（1973）、或張亭棟與榮福祥（1979）。

 

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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 (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,金鎮敬（1996）三氧化二砷注射液治療72例急性早幼粒細胞白血病.中華血液學雜志 17:58-60).

PDF：1996 張鵬 et al 三氧化二砷注射液治療72例急性早幼粒細胞白血病.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.

哈爾濱醫科大學第一臨床醫院的張鵬、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、金鎮敬(1996)總結他們自1992年至1995年用三氧化二砷（不含汞）治療130例APL病人中完成一個及以上療程的72例。初治患者完全緩解率為73%，復發患者完全緩解率為52%，與全反式維甲酸無交叉耐藥。

 

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,張亭棟,王興榕,劉旭(1988). 癌靈1號注射液對人肝癌細胞殺傷動力學研究. 腫瘤防治研究 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.(三氧化二砷治療肝細胞肝癌及其機理研究. 中華外科雜志）

PDF：2005 三氧化二砷對原發性肝癌的作用及其機理研究.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.（三氧化二砷治療結腸癌現狀 中西醫結合雜志）

PDF：2006 三氧化二砷對結腸癌作用的研究近況.pdf

 

 

 

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