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用维甲酸治疗白血病是否中国人原创?

已有 7382 次阅读 2013-2-14 09:01 |个人分类:期刊论文|系统分类:论文交流| 原创, 中国人, 白血病, 维甲酸

 

早在1986年,上海瑞金医院王振义教授就用全反式维甲酸(ATRA)治疗24例急性早幼粒细胞白血病(APL),完全缓解率高达95.8%。该成果发表在《血液》(Blood)1988年第72卷567-572页(http://bloodjournal.hematologylibrary.org/content/72/2/567.full.pdf)。

 

那么,是谁最先用维甲酸治疗白血病?在上述论文的Introduction中有这么一段话:

 

Induction of differentiation may be an alternative approach to treatment of APL. Retinoic acid (RA), an analogue of vitamin A, is one of the many agents that can induce differentiation and terminal cell division of leukemic cells in vitro.5 At present, several cases of APL treated with 13-cis RA have been reported with encouraging results.6-9 We report in vitro studies and therapeutic trials of 24 APL patients using all-trans RA.

 

 

译文:分化诱导可能是治疗APL的一种新方法。维甲酸——维生素A的一种类似物——是能离体诱导白血病细胞分化及终末分裂的众多药物之一(文献5)。目前,已报道几个用13-顺式维甲酸治疗APL的病例,并取得良好疗效(文献6-9)。我们在此报道用全反式维甲酸进行的体外研究及对24名APL患者开展的治疗试验。

 

上述5篇参考文献分别是:

 

5. Koeffler HP: Induction of differentiation of human acute myelogenous leukemia cells: Therapeutic implications. Blood 62:709, 1983 

 
6. Flynn P. Miller W, Weisdorf D, Arthur D, Banning R, Branda R: Retinoic acid treatment of acute promyelocytic leukemia: In vitro and in vivo observations. Blood 62:121 1, 1983 
 
7. Nilsson B: Probable in vivo induction of differentiation by retinoic acid of promyelocytes in acute promyelocytic leukemia. Bri Haematol 57:365, 1984 
 
8. Daenen 5, Vellenga E, van Dobbenbugh OA, Halie MR: Retinoic acid as antileukemic therapy in a patient with acute promyelocytic leukemia and Aspergillus pneumonia. Blood 67:559, I 986 
 
9. Fontana iA, Roger iS, Durham iP: The role of 13-cis retinoic acid in the remission induction of a patient with acute promyelocytic leukemia. Cancer 57:209, 1986

 

 

由此可见,用维甲酸治疗白血病并非中国人的创意,但过去国外使用的都是13-顺式维甲酸,而王振义教授使用的是全反式维甲酸。

 

在该论文的Discussion中这样写道:

 

13-cis RA and all-trans RA were equally effective in induction of differentiation in vitro.5 Our studies confirm that, in vitro, leukemic promyelocytes could be induced by all-trans RA to differentiate toward mature granulocytes.

 

 

译文:13-顺式维甲酸与全反式维甲酸在离体分化诱导中同样有效(文献5)。我们的研究证实,在体外白血病的早幼粒细胞可被全反式维甲酸诱导分化为成熟的粒细胞。

 

因此,用全反式维甲酸诱导分化的创意也不是来自中国人,但王振义教授是国际上应用全反式维甲酸治疗APL的第一人。

 

在文章的最后,还解释了为什么以往都热衷使用顺式维甲酸而不是全反式维甲酸的理由:

 

The toxicity of 1 3-cis RA is relatively lower than that of all-trans RA,25 but in our experience the side effects were well tolerated by the patients, some of whom have been taking RA for > 10 months with no severe untoward effects.

 

译文:13-顺式维甲酸的毒性比全反式维甲酸稍低(文献25),但据我们的经验,患者对其副作用都能很好地耐受,有的连续使用10个月以上仍无严重的负面效果。

 

因此,王振义教授是世界上首先报告全反式维甲酸可以成功治疗白血病的人。

 

另外,王振义教授曾与法国人Laurent Degos共同发表一篇综述,题目是“全反式维甲酸治疗急性早幼粒细胞白血病”(All trans retinoic acid in acute promyelocytic leukemia),全文发表于《癌基因》(Oncogene)2001年第20卷49期(http://www.nature.com/onc/journal/v20/n49/full/1204763a.html)。

 

Retinoids are able to induce a terminal differentiation of leukemic cell lines, such as HL60 and U937, and of short-term culture APL cells from humans (Breitman et al., 1981; Chomienne et al., 1986). An informal discussion between us (Degos and Wang, Paris, 1985) on differentiation therapy of APL using retinoids, pointed out the fact that the only available retinoid in Europe, the ethyl ester retinoid (etritinate) is not effective on APL cells (Chomienne et al., 1986). In fact the differentiation effect on fresh cells is restricted to patients with the APL subtype of non-lymphoblastic leukemia and the sensitivity of the malignant cells depends on the specific derivative, with ATRA being the most efficient drug (Chomienne et al., 1990).

All trans retinoic acid was produced in Shanghaï and first used to treat patients there (Huang et al., 1988). Following a collaborative meeting in Shanghaï in 1987, the Chinese drug was kindly provided to subsequently treat French patients (Castaigne et al., 1990).

 

以上描述说明,早在1981年和1986年,国际上已经有人报道维甲酸分别在白血病细胞株及APL短期培养细胞中诱导终末分化的研究结果。王振义教授与Laurent Degos曾在1985年就使用维甲酸对APL进行分化治疗做过非正式讨论。随后,全反式维甲酸分别在中国和法国开展了白血病的治疗,结果于1988年和1990年公开发表。

 

综上所述,维甲酸用于白血病治疗在国际上早有先例,不是中国人的原创,但将全反式维甲酸成功用于白血病的临床治疗,则是中国人首次尝试。



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