白血病bcl－2,pI7O,CD34表达的临床意义及其相关性
作者：段宝华1，刘少君2*，席雨人2
单位：段宝华(河南医科大学第二附属医院血液内科,河南 郑州 450003)；刘少君(河南医科大学第一附属医院血液内科,河南 郑州 450052)；席雨人(河南医科大学第一附属医院血液内科,河南 郑州 450052)
关键词：
癌症000214
【摘 要】目的：探讨和分析白血病bcl-2，p170，CD34表达的临床意义及其相关性。方法：用ABC免疫细胞化学法检测77例急性白血病和23例慢性粒细胞白血病bcl-2，p170，CD34的表达。结果：复发、难治急性白血病bcl-2，p170，CD34的表达率明显高于初治急性白血病；bcl-2，p170，CD34高表达的急性白血病完全缓解率显著低于不表达或低表达者；加速/急变期的慢性粒细胞白血病CD34表达高于慢性期；bcl-2高表达的阳性符合率为90.9%,略高于p170或CD34；白血病bcl-2，p170的表达有轻度正相关性(r=0.386,P<0.001)。结论：bcl-2为较敏感的临床预测指标，联合检测bcl-2,p170,CD34可能提高单一指标的预测价值。CD34可能是CML病程进展的指标。而不同多药耐药机制可能有一定的联系。关键词：白血病；bcl-2；p170；CD34；多药耐药
, http://www.100md.com
中图分类号：R733.7 文献标识码：A
文章编号：1000-467X(2000)02-0146-04
Clinical significance of expressions of bcl-2，p170，and CD34 in leukemia
DUAN Bao-hua XI Yu-ren
(Department of Hematology，second affiliated Hospital，Henan Medical University， Zhengzhou 450003，P.R. China)
LIU Shao-jun
(Department of Hematology,First Affiliated Hospital,Henan Medical University,Zhengzhou 450052,P.R. China)
, 百拇医药
【Abstract】 Objective:To study and assess the clinical significance of the expressions of bcl-2,p170,and CD34 in leukemia and their correlations. Methods:ABC immunocytochemistry was used in detection of the expressions of bcl-2,p170,and CD34 in leukemic cells from 77 cases of acute leukemia(AL)and 23 cases of chronic myeloid leukemia (CML) patients. Results:The expression rates of bcl-2,p170,and CD34 in relapsed or refractory acute leukemia were significantly higher than those in the untreated acute leukemia. The complete remission rates were significantly lower in the patients with overexpression than in those with low-/non-expression of one of the detected markers,bcl-2,p170 and CD34. The expression of CD34 in CML accelerative or excess blast phase was higher than that in chronic phase. It was found that the positive coincidence rates were 90.9% for overexpression of bcl-2,which was a little higher than that of p170 or CD34. It was showed that there was slightly positive correlation between the expression rates of bcl-2 and p170 (r=0.386,P<0.001). Conclusion:There is more sensitive predictive value of bcl-2 among these three markers. The combined detection of bcl-2,p170 and CD34 may improve the predictive value of each. It was also suggested that CD34 could be a poor indicator in the course of CML. There may be some correlation among the different MDR mechanisms.
, http://www.100md.com
Key words：Leukemia; bcl-2; p170; CD34; MDR
Multidrug resistance (MDR) of leukemic cells to chemotherapeutic agents is one of the important factors influencing the prognosis and survival of patients with leukemia.However,mechanisms of MDR in leukemic cells are very complicated,in which mdrl gene and its product p170 has been well- researched.In recent years, it was found that the blockage of apoptosis reduced by chemotherapeutic drugs, such as the increased expression of bcl-2 gene, would also result in MDR of cancer cells. Moreover, the high expression of CD34 has been shown to be relevant to the poor prognosis of leukemia. In this study, the expression of bcl- 2,p170 and CD34 in acute or chronic leukemia were detected to explore their predictive values,which might be helpful to guide the using of drugs in clinic.
, 百拇医药
1 Materials and methods
1.1 Patients and cell lines
A total of 77 patients with acute leukemia (39 primary cases,22 relapsed or refractory cases and 16 in complete remission cases;55 cases AML,22 cases ALL),23 patients with chronic myeloid leukemia(CML)(13 cases in chronic phase and 10 cases in accelerated phase or blast crisis) and 7 cases of normal controls were chosen.
HL- 60 cell line and normal colonal mucosa epithelial cell slides were positive control of bcl- 2 and p170 respectively.
, http://www.100md.com
1.2 Reagents and methods
Monoclonal antihuman antibodies against bcl-2 and CD34 were purchased from NEOMARKE Company,p170 from ZYMED Company,and ABC test kit from VECTOR Company.
Slides of fixed mononuclear cells from above patients'bone marrows were detected by ABC immunocytochemistry technique according to reference 4 and the percentage of positive cells were calculated,which contained some brown- granules in protoplasm or on the cell membrane,in 500 cells under oil- vision of microscope. Positive control and substitutive control were set in every trial.
, http://www.100md.com
1.3 Statistic
bcl- 2 and p170 were regarded as overexpression when their percentages of positive cells were over 10% ,while CD34 was over 20% (according to the condition of our test),and t-test,χ2-test and F- test were used in this study to analyze these data.
2 Results
There was no relation between the expression of bcl- 2, p170 or CD34 and the patients'age,sex,white blood cell count in the peripheral blood or the number of blast cells in the bone marrow.As shown in table 1, the results showed that the expressions of bcl- 2,p170,and CD34 in relapsed/refractory were significantly higher than those in normal controls,untreated acute leukemia and acute leukemia in complete remission(P<0.05). In CML patients,the expression of CD34 and overexpression of bcl- 2 were lower in chronic phase than in accelerated phase or blast prisis(table 2). For the patients with de novo AL treated by chemotherapy, CR rates were significantly lower in the patients with overexpression than in those with low- /non- expression of one of the detected markers (table 3). The overexpression rates of bcl- 2 and p170 were different between one and two treatment courses to CR induced by chemotherapy (table 4). The results also showed that there were different coincident rates in prediction of clinical efficacy of leukemia between the single detection and combined defection of bcl- 2, p170 or CD34 (table 5). In this study,it was found there were positive correlations between the expression rates of bcl- 2 and p170 (r=0.386, P< 0.001),bcl- 2 and CD34(r=0.376,P<0.001),and p170 and CD34(r=0.353,P< 0.002)in leukemic cells.
, http://www.100md.com
Table 1 The expression rates of bcl- 2,p170 and CD34in acute leukemia in percentage group
cases
bcl- 2
p170
CD34
+
++
+
++
+
++
, 百拇医药
relapsed/refractory*
22
12.8± 7.7
68.2
9.7± 6.1
54.6
23.5± 16.6
59.1
primary**
39
5.8± 5.7
23.1
, http://www.100md.com
6.0± 5.4
28.2
13.8± 12.5
28.2
CR＃
16
1.1± 0.9
0
2.6± 2.3
0
2.3± 2.2
0
, http://www.100md.com normal＃＃
7
0.8± 0.7
0
1.3± 1.2
0
1.7± 1.6
0
* compared with ＃or ＃＃,P<0.01；**compared with ＃or ＃＃,*compared with **,P< 0.05
+ :positive expression cells rate ++ :percentage of overexpression cases Table 2 The expression rates of bcl- 2, p170 and CD34 in chronic myeloid leukemia in percentage group
, 百拇医药
cases
bcl-2
p17
CD34
+
++
+
++
+
++
chronic phase*
13
3.3± 2.7
, 百拇医药
0
4.5± 4.0
7.7
4.1± 3.6
0
acceleated phase**
10
7.9± 6.6
30
9.2± 7.3
40.0
10.1± 8.7
, 百拇医药
10
P >0.05
P<0.05
P >0.05
P >0.05
P <0.05
P >0.05
P:* compared with ** + :positive expression cells rate ++ :percentage of overexpression cases Table 3 The relationship between the expression
of bcl- 2, p170 and CD34 and the curative
, 百拇医药
efficacy or prognosis of acute leukemia
bcl-2
p170
CD34
++
+/-
++
+/-
++
+/-
CR rate (%)
45.5
, 百拇医药
77.7
50.0
78.6
57.1
75.0
no CR and early relapsed rate(% )
81.8
29.0
78.6
25.0
25.0
32.1
, http://www.100md.com
P<0.05
P<0.05
P<0.05
P:++ compared with +/-
++：:overexpression +/-：low- /non- expression Table 4 The relationship between the expression
of bcl- 2,p170,CD34, and the number
of courses to CR in acute leukemia
one courses*two courses**
, http://www.100md.com
bcl-2 overexpression rate(%)
5.6
36.4
P<0.05
p170 overexpression rate(%)
11.1
45.5
P<0.05
CD34 overexpression rate(%)
18.7
45.5
, 百拇医药
P >0.05
P:* Compared with **Table 5 The predictive values of bcl- 2,p170 and
CD34 for clinical efficacy in acute leukemia
bcl-2
p170
CD34
bcl-2/P170/CD34
positive coincident rate(%)
, 百拇医药
90.9
78.6
84.6
100
negative coincident rate(%)
67.7
67.9
69.0
80
total coincident rate(%)
73.8
71.4
, 百拇医药
73.8
84.6
positive coincident rate=the number of positive drugresistance case/(the number of positive drugresistance+ positive nondrugresistance cases)
negative coincident rate=the number of negative drugresistance case/(the number of negative drugresistance+ negative nondrugresistance cases)
total coincident rate=(the number of positive drugresistance case+ the number of negative drugresistance cases)/the number of total cases
, 百拇医药
3 Discussion
The complexity of MDR brought certain difficulty to the forecasting of curative result or prognosis of leukemia. The research about the sensitivity or the speciality of all these factors were argureable. To evaluate and find more sensitive markers might be helpful for the diretion of treatment in clinic. In this study, it was concluded that the predictive values of p170 and CD34 in the treatmental efficacy and prognosis of leukemia were lightly lower than that of bcl- 2, but the negative coincident rates of the three markers were all low, as might be related to the existence of other poor factors,such as the proliferation of leukemic cell, the control of complication and the normal hemapoietic rehabilitation of bone marrow after chemotherapy,and other mechanisms of MDR. But it is showed that the combined detection of bcl- 2, p170 and CD34 might improve the predictive value and all of them could be indicators for the choice of chemotherapeutic agents or reversing methods. As a result, to study on the significance of combined detection of more than one marker might be the trend of further research.
, 百拇医药
So far,the effect of these markers still exists divergence in progressive course of CML. The results showed the overexpression of CD34 could be a signer of the deterioration of CML.
In present viewpoints, the mechanism of antiapoptosis gene bcl- 2 resulting in MDR is different from the mdrl gene. But in some reports,the expressions of bcl- 2 gene and mdr1 gene were all relevant to the cellular differentiation. Further study has revealed that some informative molecules in cell such as pkc,Ca2+ were participated in the regulation of the expression of bcl- 2,p170,and CD34. In this study, the findings showed the lightly positive correlation between bcl- 2 and p170. From this we supposed that there might be some relationship between them, that is to say, having partly same regulating path or regulating each other,in one or more levels. The high expression of bcl- 2 and p170 might provided the survival predomination and MDR for the leukemic stem cells and might be some causes resulting in the poor prognosis of leukemia with the overexpression of CD34. But the essence of the correlation between bcl- 2 and p170 needs further researching and clinical conformation.
, 百拇医药
通讯作者：刘少君：Tel:86-371-6979037
E-mail:ab193305@public2.zz.ha.cn
[REFERENCE]
[1] Ito Y, Tanimoto M, Kumazawa T, et al. Increased P-glycoprotein expression and multidrug-resistance gene(mdrl)amplification are infrequently found in fresh acute leukemia cells. Sequential analysis of 15 cases at initial presentation and relapsedtaged [J]. Cancer,1989,63:1534～1538.
[2] Miyashita T, Reed JC. Bcl-2 oncoprotein blocks chemotherapy induced apoptosis in a human leukemia cell line [J]. Blood,1993,81(1):151～157.
, 百拇医药
[3] Zou P, Xiang J P, Chen Z C, et al. Study on the expression of CD34 in acute myeloid leukemia [J]. Chinese Jonrnal of Hematology, 1994,15(7):339.
[4] Situ ZQ, Wu JZ. The immunotistochemistry of cultural cells. In: Situ Z Q, Wu J Z eds [M]. Cultury of cell,1996: 202.
[5] Lotem J, Sachs L. Regulation by bcl-2, c-myc and p53 of susceptibility to induction of apoptosis by heat shock and cancer chemotherapy compounds in differentiation-competent and-defective myeloid leukemic cells [J]. Cell Growth Differ,1993,4:41～47.
, 百拇医药
[6] Bradury DA, Zhu YM, Russell NH. Bcl-2 expression in acute myeloblastic leukemia: relationship with autonomons growth and CD34 antigen expression [J] . Leuk Lymphoma, 1997, 24(3～ 4):221～228.
[7] Chaudhary PM, Roninson IB. Expression and activity of P-glocoprotein, a multidrug efflux pump, in human hematopoietic stem cells [J]. Cell, 1991,66:85～94.
[8] Rinaudo MS, Su K,Falk LA, et al. Human interleukin 3 receptor modulates bcl 2 mRNA and protein levels through protein kinase C in TF 1 cells [J]. Blood,1995,86(1):80～88.
, 百拇医药
[9] Fackler MJ, Civin CI, May WS, et al. Up-regulation of surface CD34 is associated with protein kinase C-mediated hyperphosphonylation of CD34 [J]. J Biol Chem, 1992, 267:17540～17546.
[10] Beck J, Handgretinger R, Klingebiel T, et al. Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML [J]. Leukemia, 1996,10:426～433.
收稿日期：1999-01-08；修回日期：1999-12-10, 百拇医药
单位：段宝华(河南医科大学第二附属医院血液内科,河南 郑州 450003)；刘少君(河南医科大学第一附属医院血液内科,河南 郑州 450052)；席雨人(河南医科大学第一附属医院血液内科,河南 郑州 450052)
关键词：
癌症000214
【摘 要】目的：探讨和分析白血病bcl-2，p170，CD34表达的临床意义及其相关性。方法：用ABC免疫细胞化学法检测77例急性白血病和23例慢性粒细胞白血病bcl-2，p170，CD34的表达。结果：复发、难治急性白血病bcl-2，p170，CD34的表达率明显高于初治急性白血病；bcl-2，p170，CD34高表达的急性白血病完全缓解率显著低于不表达或低表达者；加速/急变期的慢性粒细胞白血病CD34表达高于慢性期；bcl-2高表达的阳性符合率为90.9%,略高于p170或CD34；白血病bcl-2，p170的表达有轻度正相关性(r=0.386,P<0.001)。结论：bcl-2为较敏感的临床预测指标，联合检测bcl-2,p170,CD34可能提高单一指标的预测价值。CD34可能是CML病程进展的指标。而不同多药耐药机制可能有一定的联系。关键词：白血病；bcl-2；p170；CD34；多药耐药
, http://www.100md.com
中图分类号：R733.7 文献标识码：A
文章编号：1000-467X(2000)02-0146-04
Clinical significance of expressions of bcl-2，p170，and CD34 in leukemia
DUAN Bao-hua XI Yu-ren
(Department of Hematology，second affiliated Hospital，Henan Medical University， Zhengzhou 450003，P.R. China)
LIU Shao-jun
(Department of Hematology,First Affiliated Hospital,Henan Medical University,Zhengzhou 450052,P.R. China)
, 百拇医药
【Abstract】 Objective:To study and assess the clinical significance of the expressions of bcl-2,p170,and CD34 in leukemia and their correlations. Methods:ABC immunocytochemistry was used in detection of the expressions of bcl-2,p170,and CD34 in leukemic cells from 77 cases of acute leukemia(AL)and 23 cases of chronic myeloid leukemia (CML) patients. Results:The expression rates of bcl-2,p170,and CD34 in relapsed or refractory acute leukemia were significantly higher than those in the untreated acute leukemia. The complete remission rates were significantly lower in the patients with overexpression than in those with low-/non-expression of one of the detected markers,bcl-2,p170 and CD34. The expression of CD34 in CML accelerative or excess blast phase was higher than that in chronic phase. It was found that the positive coincidence rates were 90.9% for overexpression of bcl-2,which was a little higher than that of p170 or CD34. It was showed that there was slightly positive correlation between the expression rates of bcl-2 and p170 (r=0.386,P<0.001). Conclusion:There is more sensitive predictive value of bcl-2 among these three markers. The combined detection of bcl-2,p170 and CD34 may improve the predictive value of each. It was also suggested that CD34 could be a poor indicator in the course of CML. There may be some correlation among the different MDR mechanisms.
, http://www.100md.com
Key words：Leukemia; bcl-2; p170; CD34; MDR
Multidrug resistance (MDR) of leukemic cells to chemotherapeutic agents is one of the important factors influencing the prognosis and survival of patients with leukemia.However,mechanisms of MDR in leukemic cells are very complicated,in which mdrl gene and its product p170 has been well- researched.In recent years, it was found that the blockage of apoptosis reduced by chemotherapeutic drugs, such as the increased expression of bcl-2 gene, would also result in MDR of cancer cells. Moreover, the high expression of CD34 has been shown to be relevant to the poor prognosis of leukemia. In this study, the expression of bcl- 2,p170 and CD34 in acute or chronic leukemia were detected to explore their predictive values,which might be helpful to guide the using of drugs in clinic.
, 百拇医药
1 Materials and methods
1.1 Patients and cell lines
A total of 77 patients with acute leukemia (39 primary cases,22 relapsed or refractory cases and 16 in complete remission cases;55 cases AML,22 cases ALL),23 patients with chronic myeloid leukemia(CML)(13 cases in chronic phase and 10 cases in accelerated phase or blast crisis) and 7 cases of normal controls were chosen.
HL- 60 cell line and normal colonal mucosa epithelial cell slides were positive control of bcl- 2 and p170 respectively.
, http://www.100md.com
1.2 Reagents and methods
Monoclonal antihuman antibodies against bcl-2 and CD34 were purchased from NEOMARKE Company,p170 from ZYMED Company,and ABC test kit from VECTOR Company.
Slides of fixed mononuclear cells from above patients'bone marrows were detected by ABC immunocytochemistry technique according to reference 4 and the percentage of positive cells were calculated,which contained some brown- granules in protoplasm or on the cell membrane,in 500 cells under oil- vision of microscope. Positive control and substitutive control were set in every trial.
, http://www.100md.com
1.3 Statistic
bcl- 2 and p170 were regarded as overexpression when their percentages of positive cells were over 10% ,while CD34 was over 20% (according to the condition of our test),and t-test,χ2-test and F- test were used in this study to analyze these data.
2 Results
There was no relation between the expression of bcl- 2, p170 or CD34 and the patients'age,sex,white blood cell count in the peripheral blood or the number of blast cells in the bone marrow.As shown in table 1, the results showed that the expressions of bcl- 2,p170,and CD34 in relapsed/refractory were significantly higher than those in normal controls,untreated acute leukemia and acute leukemia in complete remission(P<0.05). In CML patients,the expression of CD34 and overexpression of bcl- 2 were lower in chronic phase than in accelerated phase or blast prisis(table 2). For the patients with de novo AL treated by chemotherapy, CR rates were significantly lower in the patients with overexpression than in those with low- /non- expression of one of the detected markers (table 3). The overexpression rates of bcl- 2 and p170 were different between one and two treatment courses to CR induced by chemotherapy (table 4). The results also showed that there were different coincident rates in prediction of clinical efficacy of leukemia between the single detection and combined defection of bcl- 2, p170 or CD34 (table 5). In this study,it was found there were positive correlations between the expression rates of bcl- 2 and p170 (r=0.386, P< 0.001),bcl- 2 and CD34(r=0.376,P<0.001),and p170 and CD34(r=0.353,P< 0.002)in leukemic cells.
, http://www.100md.com
Table 1 The expression rates of bcl- 2,p170 and CD34in acute leukemia in percentage group
cases
bcl- 2
p170
CD34
+
++
+
++
+
++
, 百拇医药
relapsed/refractory*
22
12.8± 7.7
68.2
9.7± 6.1
54.6
23.5± 16.6
59.1
primary**
39
5.8± 5.7
23.1
, http://www.100md.com
6.0± 5.4
28.2
13.8± 12.5
28.2
CR＃
16
1.1± 0.9
0
2.6± 2.3
0
2.3± 2.2
0
, http://www.100md.com normal＃＃
7
0.8± 0.7
0
1.3± 1.2
0
1.7± 1.6
0
* compared with ＃or ＃＃,P<0.01；**compared with ＃or ＃＃,*compared with **,P< 0.05
+ :positive expression cells rate ++ :percentage of overexpression cases Table 2 The expression rates of bcl- 2, p170 and CD34 in chronic myeloid leukemia in percentage group
, 百拇医药
cases
bcl-2
p17
CD34
+
++
+
++
+
++
chronic phase*
13
3.3± 2.7
, 百拇医药
0
4.5± 4.0
7.7
4.1± 3.6
0
acceleated phase**
10
7.9± 6.6
30
9.2± 7.3
40.0
10.1± 8.7
, 百拇医药
10
P >0.05
P<0.05
P >0.05
P >0.05
P <0.05
P >0.05
P:* compared with ** + :positive expression cells rate ++ :percentage of overexpression cases Table 3 The relationship between the expression
of bcl- 2, p170 and CD34 and the curative
, 百拇医药
efficacy or prognosis of acute leukemia
bcl-2
p170
CD34
++
+/-
++
+/-
++
+/-
CR rate (%)
45.5
, 百拇医药
77.7
50.0
78.6
57.1
75.0
no CR and early relapsed rate(% )
81.8
29.0
78.6
25.0
25.0
32.1
, http://www.100md.com
P<0.05
P<0.05
P<0.05
P:++ compared with +/-
++：:overexpression +/-：low- /non- expression Table 4 The relationship between the expression
of bcl- 2,p170,CD34, and the number
of courses to CR in acute leukemia
one courses*two courses**
, http://www.100md.com
bcl-2 overexpression rate(%)
5.6
36.4
P<0.05
p170 overexpression rate(%)
11.1
45.5
P<0.05
CD34 overexpression rate(%)
18.7
45.5
, 百拇医药
P >0.05
P:* Compared with **Table 5 The predictive values of bcl- 2,p170 and
CD34 for clinical efficacy in acute leukemia
bcl-2
p170
CD34
bcl-2/P170/CD34
positive coincident rate(%)
, 百拇医药
90.9
78.6
84.6
100
negative coincident rate(%)
67.7
67.9
69.0
80
total coincident rate(%)
73.8
71.4
, 百拇医药
73.8
84.6
positive coincident rate=the number of positive drugresistance case/(the number of positive drugresistance+ positive nondrugresistance cases)
negative coincident rate=the number of negative drugresistance case/(the number of negative drugresistance+ negative nondrugresistance cases)
total coincident rate=(the number of positive drugresistance case+ the number of negative drugresistance cases)/the number of total cases
, 百拇医药
3 Discussion
The complexity of MDR brought certain difficulty to the forecasting of curative result or prognosis of leukemia. The research about the sensitivity or the speciality of all these factors were argureable. To evaluate and find more sensitive markers might be helpful for the diretion of treatment in clinic. In this study, it was concluded that the predictive values of p170 and CD34 in the treatmental efficacy and prognosis of leukemia were lightly lower than that of bcl- 2, but the negative coincident rates of the three markers were all low, as might be related to the existence of other poor factors,such as the proliferation of leukemic cell, the control of complication and the normal hemapoietic rehabilitation of bone marrow after chemotherapy,and other mechanisms of MDR. But it is showed that the combined detection of bcl- 2, p170 and CD34 might improve the predictive value and all of them could be indicators for the choice of chemotherapeutic agents or reversing methods. As a result, to study on the significance of combined detection of more than one marker might be the trend of further research.
, 百拇医药
So far,the effect of these markers still exists divergence in progressive course of CML. The results showed the overexpression of CD34 could be a signer of the deterioration of CML.
In present viewpoints, the mechanism of antiapoptosis gene bcl- 2 resulting in MDR is different from the mdrl gene. But in some reports,the expressions of bcl- 2 gene and mdr1 gene were all relevant to the cellular differentiation. Further study has revealed that some informative molecules in cell such as pkc,Ca2+ were participated in the regulation of the expression of bcl- 2,p170,and CD34. In this study, the findings showed the lightly positive correlation between bcl- 2 and p170. From this we supposed that there might be some relationship between them, that is to say, having partly same regulating path or regulating each other,in one or more levels. The high expression of bcl- 2 and p170 might provided the survival predomination and MDR for the leukemic stem cells and might be some causes resulting in the poor prognosis of leukemia with the overexpression of CD34. But the essence of the correlation between bcl- 2 and p170 needs further researching and clinical conformation.
, 百拇医药
通讯作者：刘少君：Tel:86-371-6979037
E-mail:ab193305@public2.zz.ha.cn
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收稿日期：1999-01-08；修回日期：1999-12-10, 百拇医药