新药二乙酰己二胺对骨髓增生异常综合征的临床疗效评价及机理初探
摘要
骨髓增生异常综合征(myelodysplastic syndrome，MDS)是一组造血干细胞克隆性疾病，其特征性病理生理改变是克隆性造血干/祖细胞发育异常(dysplasia)和无效造血(ineffective hematopoiesis)。表现为骨髓增生异常但伴外周血血细胞减少，部分有转变为急性髓系白血病(AML)倾向。
MDS的诊断和分型主要依据外周血和骨髓的形态学改变，WHO分型结合了临床、病因以及细胞遗传性研究结果，MDS国际预后积分系统(IPSS)使用骨髓原始细胞％、骨髓造血细胞染色体核型和外周血细胞减少等作为预后参数，将MDS分为低危、中危Ⅰ、中危Ⅱ和高危四个危险度组，对患者中位生存期及转白时间判定具有意义，这些诊断标准和分型有助于临床医生选择MDS治疗方法和判断预后。由于MDS发病机制不明以及其异质性，目前临床上低危MDS主要有支持治疗、造血生长因子治疗以及免疫治疗等方法，而高危MDS的药物治疗效果均不甚理想。异基因造血干细胞移植是目前MDS唯一有治愈可能的方法，但是由于多数MDS患者为老年病人以及移植并发症多，只有一小部分病人有移植适应症，而目前在用或者研究的药物反应率不到20％，治疗效果均不甚理想。目前研究较多的用于改善MDS反应率和生存率的药物如低甲基化因子5-氮杂胞苷、地西他滨以及反应停、lenalidomide、infliximab等报道有较好的反应，其他还有很多药物正在研究中。
二乙酰己二胺是我国自主研发的国家一类新药，前期研究显示其有良好的诱导分化作用，可以使恶性细胞分化而丧失克隆生长能力，Ⅰ期临床试验显示其对MDS有令人欣喜的疗效。为了进一步探讨其对高危MDS的疗效以及作用机理，我们分别进行了体内和体外试验。
在体内试验中，我们选择初诊的3例高危MDS患者为受试者，分别给予CAHB24g/(m~2·d)，连续给药10天为1个疗程，间歇28-42天，血象基本恢复后进行相同剂量的第二疗程，每例受试者完成2个疗程后观察疗效。结果发现3例患者血象改善不明显，骨髓象提示用药后原始细胞比例明显下降(分别下降48.1％，58.7％和81.2％)，其中2例下降50％以上，没有观察到严重不良反应。因此CAHB使得此类患者骨髓原始细胞比例不同程度的下降，短期疗效值得肯定。
在体外试验中，我们用CAHB处理MDS-RAEB细胞株MUTZ-1细胞，利用MTT法、流式细胞仪以及半定量RT-PCR检测CAHB对细胞增殖和凋亡以及凋亡相关基因survivin的表达的影响。MTT结果显示随着CAHB药物浓度的增加和作用时间的延长，MUTZ-1细胞增殖明显受到抑制，24h、48h、72h的半数抑制浓度分别为16.08±3.13mmol/L、5.60±0.21mmol/L和3.83±0.22mmol/L(P＜0.05)。流式细胞仪检测发现CAHB能够诱导MUTZ-1细胞凋亡，且具有浓度依赖性，不同浓度(0，2.5，5，10mmol/L)的CAHB作用于MUTZ-1细胞24h的凋亡率分别为4.64±1.19％，11.64±3.43％，16.52±1.53％，34.82±1.81％(P＜0.05)。RT-PCR半定量CAHB处理MUTZ-1细胞24h后凋亡相关基因survivin的表达，发现随着CAHB浓度增加(0，1.25，2.5，5mmol/L)，survivin表达量明显下调，survivin/GADPH的值分别为0.95±0.02，0.87±0.01，0.79±0.03，0.72±0.01(P＜0.05)。
因此，二乙酰二胺治疗高危MDS的初步疗效肯定，且不良反应相对轻微，其
药物作用机制可能与抑制细胞增殖、促进凋亡、降低细胞survivin基因表达有关。
Myelodysplastic syndrome (MDS) is a group of highly heterogeneous disorders characterized by cytopenia, myeloid cell dysplasia, and frequent transformation to acute myeloid leukemia. It occurs at a high incidence in the elderly population. The molecular pathogenesis of the disease is poorly understood and its prognosis is poor.
The diagnosis and classification of MDS are mainly based on the morphological features of blood and bone marrow cells in conjunction with other ancillary studies. The World Health Organization (WHO) working group has proposed a classification system that takes into account the clinical, etiological, and cytogenetic data. The International Scoring System for Evaluating Prognosis (IPSS), which has proven to be highly useful for this purpose, is a risk-based classification system for MDS based on cytogenetic abnormalities and can be used to guide therapeutic choice. For MDS patients with low IPSS scores (low-risk), appropriate treatment includes supportive care, hematopoietic growth factors, and immunomodulatory drugs. For those with high IPSS scores, chemotherapy is appropriate at low or intense doses. Until recently, the vast majority of MDS patients were treated with supportive therapy alone, such as transfusions. Allogeneic stem cell transplantation (SCT) has the potential for cure,
although its role has been limited due to the age and comorbidity of MDS patients. Response to most therapies occurs slowly and sometimes months elapse before a response can be observed. The response rate for most drugs remains less than 20%. In the last few years, new agents such as 5-azacytidine, decitabine, thalidomide, lenalidomide, and infliximab have shown promising efficacy and tolerability in clinical trials. It can be challenging for a clinician to choose the most appropriate treatment for an individual patient.
Here we discuss a new agent, CAHB, for MDS treatment. CAHB is a differentiation inducer and showed a good response in phase I clinical trail. We used it to treat 3 high risk MDS patients for two courses and the results were encouraging. Though the peripheral blood cells of the three patients were not improved, all of them had a decrease in bone marrow blasts without severe side effect, the fall. percentage were 48.1 %, 58.7% and 81.2% respectively.
In order to analyze the inhibitory effect of CAHB on the growth of human MDS-RAEB cell line MUTZ-1 and to explore the possible cellular and molecular mechanism, we used MTT assay, flow cytometry, and RT-PCR methods. MTT assay showed treatment with CAHB remarkably inhibited the growth of MUTZ-1 cells in a dose-dependent and time-dependent manner. The IC_(50) at 24 h, 48 h, and 72 h were 16.08±3.13mmol/L、5.60±0.21mmol/L, and 3.83 ±
0.22mmol/L, respectively. Flow cytometry proved MUTZ-1 cells had a significant dose-dependent apoptosis after cultured with CAHB (0, 2.5, 5, 10mmol/L) for 24 h, . After treatment with CAHB (0, 1.25, 2.5, 5mmol/L), the mRNA expression of survivin gene was decreased (survivin/GADPH ratio:0.95±0.02, 0.87±0.01, 0.79±0.03, 0.72± 0.01) as the CAHB dose (0, 1.25, 2.5, 5mmol/L) rising by RT-PCR Therefore, CAHB could inhibit MUTZ-1 cell growth and survivin gene may play a role in the apoptosis of MUTZ-1 cells induced by CAHB.
We conclude that CAHB may serve as a novel agent for high risk MDS, although the underlying mechanism needs long term studies with a larger number of cases.
MDS的诊断和分型主要依据外周血和骨髓的形态学改变，WHO分型结合了临床、病因以及细胞遗传性研究结果，MDS国际预后积分系统(IPSS)使用骨髓原始细胞％、骨髓造血细胞染色体核型和外周血细胞减少等作为预后参数，将MDS分为低危、中危Ⅰ、中危Ⅱ和高危四个危险度组，对患者中位生存期及转白时间判定具有意义，这些诊断标准和分型有助于临床医生选择MDS治疗方法和判断预后。由于MDS发病机制不明以及其异质性，目前临床上低危MDS主要有支持治疗、造血生长因子治疗以及免疫治疗等方法，而高危MDS的药物治疗效果均不甚理想。异基因造血干细胞移植是目前MDS唯一有治愈可能的方法，但是由于多数MDS患者为老年病人以及移植并发症多，只有一小部分病人有移植适应症，而目前在用或者研究的药物反应率不到20％，治疗效果均不甚理想。目前研究较多的用于改善MDS反应率和生存率的药物如低甲基化因子5-氮杂胞苷、地西他滨以及反应停、lenalidomide、infliximab等报道有较好的反应，其他还有很多药物正在研究中。
二乙酰己二胺是我国自主研发的国家一类新药，前期研究显示其有良好的诱导分化作用，可以使恶性细胞分化而丧失克隆生长能力，Ⅰ期临床试验显示其对MDS有令人欣喜的疗效。为了进一步探讨其对高危MDS的疗效以及作用机理，我们分别进行了体内和体外试验。
在体内试验中，我们选择初诊的3例高危MDS患者为受试者，分别给予CAHB24g/(m~2·d)，连续给药10天为1个疗程，间歇28-42天，血象基本恢复后进行相同剂量的第二疗程，每例受试者完成2个疗程后观察疗效。结果发现3例患者血象改善不明显，骨髓象提示用药后原始细胞比例明显下降(分别下降48.1％，58.7％和81.2％)，其中2例下降50％以上，没有观察到严重不良反应。因此CAHB使得此类患者骨髓原始细胞比例不同程度的下降，短期疗效值得肯定。
在体外试验中，我们用CAHB处理MDS-RAEB细胞株MUTZ-1细胞，利用MTT法、流式细胞仪以及半定量RT-PCR检测CAHB对细胞增殖和凋亡以及凋亡相关基因survivin的表达的影响。MTT结果显示随着CAHB药物浓度的增加和作用时间的延长，MUTZ-1细胞增殖明显受到抑制，24h、48h、72h的半数抑制浓度分别为16.08±3.13mmol/L、5.60±0.21mmol/L和3.83±0.22mmol/L(P＜0.05)。流式细胞仪检测发现CAHB能够诱导MUTZ-1细胞凋亡，且具有浓度依赖性，不同浓度(0，2.5，5，10mmol/L)的CAHB作用于MUTZ-1细胞24h的凋亡率分别为4.64±1.19％，11.64±3.43％，16.52±1.53％，34.82±1.81％(P＜0.05)。RT-PCR半定量CAHB处理MUTZ-1细胞24h后凋亡相关基因survivin的表达，发现随着CAHB浓度增加(0，1.25，2.5，5mmol/L)，survivin表达量明显下调，survivin/GADPH的值分别为0.95±0.02，0.87±0.01，0.79±0.03，0.72±0.01(P＜0.05)。
因此，二乙酰二胺治疗高危MDS的初步疗效肯定，且不良反应相对轻微，其
药物作用机制可能与抑制细胞增殖、促进凋亡、降低细胞survivin基因表达有关。
Myelodysplastic syndrome (MDS) is a group of highly heterogeneous disorders characterized by cytopenia, myeloid cell dysplasia, and frequent transformation to acute myeloid leukemia. It occurs at a high incidence in the elderly population. The molecular pathogenesis of the disease is poorly understood and its prognosis is poor.
The diagnosis and classification of MDS are mainly based on the morphological features of blood and bone marrow cells in conjunction with other ancillary studies. The World Health Organization (WHO) working group has proposed a classification system that takes into account the clinical, etiological, and cytogenetic data. The International Scoring System for Evaluating Prognosis (IPSS), which has proven to be highly useful for this purpose, is a risk-based classification system for MDS based on cytogenetic abnormalities and can be used to guide therapeutic choice. For MDS patients with low IPSS scores (low-risk), appropriate treatment includes supportive care, hematopoietic growth factors, and immunomodulatory drugs. For those with high IPSS scores, chemotherapy is appropriate at low or intense doses. Until recently, the vast majority of MDS patients were treated with supportive therapy alone, such as transfusions. Allogeneic stem cell transplantation (SCT) has the potential for cure,
although its role has been limited due to the age and comorbidity of MDS patients. Response to most therapies occurs slowly and sometimes months elapse before a response can be observed. The response rate for most drugs remains less than 20%. In the last few years, new agents such as 5-azacytidine, decitabine, thalidomide, lenalidomide, and infliximab have shown promising efficacy and tolerability in clinical trials. It can be challenging for a clinician to choose the most appropriate treatment for an individual patient.
Here we discuss a new agent, CAHB, for MDS treatment. CAHB is a differentiation inducer and showed a good response in phase I clinical trail. We used it to treat 3 high risk MDS patients for two courses and the results were encouraging. Though the peripheral blood cells of the three patients were not improved, all of them had a decrease in bone marrow blasts without severe side effect, the fall. percentage were 48.1 %, 58.7% and 81.2% respectively.
In order to analyze the inhibitory effect of CAHB on the growth of human MDS-RAEB cell line MUTZ-1 and to explore the possible cellular and molecular mechanism, we used MTT assay, flow cytometry, and RT-PCR methods. MTT assay showed treatment with CAHB remarkably inhibited the growth of MUTZ-1 cells in a dose-dependent and time-dependent manner. The IC_(50) at 24 h, 48 h, and 72 h were 16.08±3.13mmol/L、5.60±0.21mmol/L, and 3.83 ±
0.22mmol/L, respectively. Flow cytometry proved MUTZ-1 cells had a significant dose-dependent apoptosis after cultured with CAHB (0, 2.5, 5, 10mmol/L) for 24 h, . After treatment with CAHB (0, 1.25, 2.5, 5mmol/L), the mRNA expression of survivin gene was decreased (survivin/GADPH ratio:0.95±0.02, 0.87±0.01, 0.79±0.03, 0.72± 0.01) as the CAHB dose (0, 1.25, 2.5, 5mmol/L) rising by RT-PCR Therefore, CAHB could inhibit MUTZ-1 cell growth and survivin gene may play a role in the apoptosis of MUTZ-1 cells induced by CAHB.
We conclude that CAHB may serve as a novel agent for high risk MDS, although the underlying mechanism needs long term studies with a larger number of cases.
引文
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