Search Article Keyword:  
PubMed Submission Abstarct PDF Cited  Click Count: 180 DownLoad Count: 226 

ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2003 September;9(9):1963-1967

Experimental study of anti-tumor effects of polysaccharides from Angelica sinensis

Peng Shang, Ai-Rong Qian, Tie-Hong Yang, Min Jia, Qi-Bing Mei, Chi-Hin Cho, Wen-Ming Zhao, Zhi-Nan Chen


Peng Shang, Wen-Ming Zhao, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
Peng Shang, Ai-Rong Qian, Zhi-Nan Chen, Department of Cell Biology, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Tie-Hong Yang, Min Jia, Qi-Bing Mei, Department of Pharmacology, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Chi-Hin Cho, Department of Pharmacology, Faculty of Medicine, University of Hong Kong, Hong Kong, China
Supported by RGC grant from the University of Hong Kong and the Hong Kong Research Grant Council (HKU7257-98M), and grants from the Hi-Tech Research & Development Program of China (2001AA215061)
Correspondence to: Dr. Zhi-Nan Chen, Department of Cell Biology, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China.  chcerc2@fmmu.edu.cn. Dr. Qi-Bing Mei, Department of Pharmacology, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China.  qbmei@hotmail.com
Telephone: +86-29-3374547
Received: 2003-04-07    Accepted: 2003-05-21

Abstract
AIM: To investigate the in vivo anti-tumor effects of total polysaccharide (AP-0) isolated from Angelica sinensis (Oliv.) Diels (Danggui) on mice and the in vitro inhibitory effects of AP-0 and its sub-constituents (AP-1, AP-2 and AP-3) on invasion and metastasis of human hepatocellular carcinoma.

METHODS: Three kinds of murine tumor models in vivo, sarcoma 180 (S180), leukemia L1210 and Ehrlich ascitic cancer (EAC) were employed to investigate the anti-tumor effects of AP-0. For each kind of tumor model, three experimental groups were respectively given AP-0 at doses of 30, 100 and 300 mg/kg by ip once a day for 10 days. Positive control groups were respectively given Cy at a dose of 30 mg/kg for S180 and leukemia L1210, and 5-FU at a dose of 20 mg/kg for EAC. On d 11, mice bearing S180 were sacrificed and the masses of tumors, spleens and thymus were weighed. The average living days of mice bearing EAC and of mice bearing L1210 were observed, and the rates of life prolongation of each treatment were calculated, respectively. The inhibitory effects of APs on hepatoma invasion and metastasis in vitro were investigated by employing human hepatocellular carcinoma cell line (HHCC) with the Matrigel invasion chamber, adhesion to extracelluler matrix and chemotatic migration tests, respectively.

RESULTS: AP-0 had no obviously inhibitory effect on the growth of S180, but it could significantly decrease the thymus weights of the mice bearing S180. AP-0 could significantly reduce the production of ascitic liquids and prolong the life of mice bearing EAC. AP-0 could also increase the survival time of mice bearing L1210. AP-0 and AP-2 had significantly inhibitory effects on the invasion of HHCC into the Matrigel reconstituted basement membrane with the inhibitory rates of 56.4 % and 68.3 %, respectively. AP-0, AP-1, AP-2 and AP-3 could influence the adhesion of HHCC to extracellular matrix proteins (Matrigel and fibronectin) at different degrees, among them only AP-3 had significant blocking effect on the adhesion of HHCC to fibronectin with an inhibitory rate of 30.3 %. AP-0, AP-1 and AP-3 could partially inhibit the chemotactic migration abilities of HHCC.

CONCLUSION: The experimental findings suggest that total polysaccharide of Angelica sinensis (Oliv.) Diels (Chinese Danggui) possesses anti-tumor effects on experimental tumor models in vivo and inhibitory effects on invasion and metastasis of hepatocellular carcinoma cells in vitro.

Shang P, Qian AR, Yang TH, Jia M, Mei QB, Cho CH, Zhao WM, Chen ZN. Experimental study of anti-tumor effects of polysaccharides from Angelica sinensis. World J Gastroenterol  2003; 9(9): 1963-1967
http://www.wjgnet.com/1007-9327/9/1963.asp

INTRODUCTION
The Chinese herbal medicine Danggui, root of Angelica sinensis (Oliv.) is widely used in traditional Chinese medical therapy of various diseases as well as a healthful food tonic and spice for thousands of years. Being called the
"female ginseng", it is excellent as an all purpose women’s herb[1]. Danggui can be used for anemia due to chronic renal failure (CRF)[2] and can enhance hematopoiesis by stimulating macrophages, fibroblasts, lymphocytes in hematopoietic inductive microenvironment and muscle tissue to secrete hematopoietic growth factors. Gastrointestinal protective effects[3,4] and the mechanism[5,6] of polysaccharides from Angelica sinensis in rats have been reported. Effects of Angelica polysaccharides on blood coagulation and platelet aggregation[7] and the protective effect of the polysaccharides-enriched fraction from Angelica sinensis on hepatic injury[8] were also studied. A low molecular weight polysaccharide from Angelica sinensis (Oliv.) Diels showed strong anti-tumor activity on Ehrlich ascitic cancer bearing mice and also exhibited immunostimulating activities, both in vitro and in vivo[9] (Choy et al. Am J Chin Med, 1994;22:137). Polysaccharides from three kinds of edible fungi showed inhibitory activities on the proliferation of human hepatoma SMMC-7721 cells and mouse implanted S180 tumor[10]. Apoptosis of hepatoma cells SMMC-7721 could be induced by polysaccharides from Ginkgo biloba seeds[11]. In China, hepatocellular carcinoma with high invasiveness and recurrence has ranked second of cancer mortality since 1990s. Anti-invasion and metastasis is currently one of the major targets of hepatoma studies[12,13]. Some polysaccharides involve in the process of tumor invasion and progression, such as heparin, heparan sulfate and hyaluronan[14-16]. The anti-metastasis effects and their pharmacological mechanisms of modified citrus pectin[17] and protein-bound polysaccharide (PSK) have been studied recently[18-20]. However, the anti-tumor effects on other kinds of tumors and the anti-invasion and metastasis effects of polysaccharides from Angelica sinensis (Oliv.) Diels have not been studied. In the present study, the anti-tumor effects of total polysaccharide (AP-0) on mice bearing transplanted sarcoma 180, leukemia L1210 and Ehrlich ascitic cancer (EAC) were investigated. The in vitro inhibitory effects of AP-0 and its sub-constituents, AP-1, AP-2 and AP-3 on the abilities of invasion and metastasis of human hepatocellular carcinoma were also tested by employing HHCC cell line.

MATERIALS AND METHODS
Animals and cell lines
Male BALB/c mice, weighing 18-22 g, were used in S180 and EAC experiments, and male DBA/2 mice, weighing 18-22 g, were used in L1210 experiment. All the mice were raised in a clear room with controlled temperature and humidity. Animals were free to drink tap water. Human hepatocellular carcinoma cell line (HHCC) was purchased from Type Culture Collection of Chinese Academy of Sciences, Shanghai, China. Human embryo dermal fibroblast cell line (Fb) was kindly presented by Dr. JT Han (Department of Plastic Surgery, Fourth Military Medical University).

Polysaccharides from Angelica sinensis
Fresh roots of Angelica sinensis (Oliv.) were picked in autumn from Minxian County, Gansu Province, China. Total polysaccharide (AP-0) was isolated by ethanol precipitation after boiling water extraction. The sub-constituents, AP-1, AP-2 and AP-3 from AP-0 were obtained by multi-precipitation treated with CTAB, H3BO3, NaOH, acetic acid and ethanol according to Yamada et al[21]. The physical-chemical characteristics of APs were analyzed and determined (Shang P, et al. Disi Junyi Daxue Xuebao, 2001;22:1311; Chin Pharmaceutical J,2000;35:332). The contents of total carbohydrate, uronic acids and proteins in AP-0, AP-1, AP-2 and AP-3 were 97.0 %, 21.0 % and 3.0 %; 97.0 %, 17.2 % and 3.0 %; 83.0 %, 25.7 % and 17 %; 97.0 %, 8.6 % and 3 %, respectively. All of APs solution was dispensed with sterile N S in the laminar flow bench.

Mice transplanted tumor models and Angelica polysaccharide (AP-0) treatments
Mice model of S180  was established by inoculating 5×106 S180 cells into left armpit of each mouse. From the next day following tumor cells inoculation (d 1) to the 10th day (d 10), mice in 3 experimental groups were administrated ip AP-0 at doses of 30, 100 and 300 mg/kg, once daily, respectively. Positive and negative control groups were given Cy at a dose of 30 mg/kg and N S of 20 mg/kg, once daily, respectively. On d 11, the mice were sacrificed, and the weights of tumor, spleen and thymus were recorded. Mice model of EAC was made by injecting ip 2.5×106 EAC cells into each mouse. From the second day of tumor cells inoculation (d 1) to the 10th day (d 10), mice in 3 experimental groups were given AP-0 ip at doses of 30, 100 and 300 mg/kg, once daily, respectively. Positive and negative control groups were given 5-FU at a dose of 20 mg/kg and N.S. of 20 mg/kg, respectively. The average survival time of less than 60 days each group was observed and the effects  of AP-0 on prolongation were calculated. Mice model of L1210 was made by injecting ip 1×105 L1210 cells into each mouse. From the next day of tumor cells inoculation (d 1) to the 10th day (d 10), mice in 3 experimental groups were given AP-0 ip at doses of 30, 100 and 300 mg/kg, once daily, respectively. Positive and negative control groups were given Cy at a dose of 30 mg/kg and NS of 20 mg/kg. The average survival time of less than 30 days of each group was observed and the rates of life prolongation were calculated.

Anti-invasion tests of angelica polysaccharides in vitro
Experimental methods employed in this part were based on previous report[22] with a slight modification.
AP-0-AP-3’s inhibitory effects on HHCC invasion into reconstituted basement membrane  Each inner membrane of Millicell chamber (Millipore, USA) was paved with 40 mL Matrigel (BD Bioscience, USA) and dried in the laminar bench at room temperature. The Matrigel-Millicells of co-cultured HHCC and Fb, with each Milicell containing 150 mL (1.5×105) cells cultured in DMEM supplemented with 1 mL/L bovine calf serum (BCS), were put into 24-well microplates (Nunc, Sweden) containing 10 mg fibronectin (FN, GIBCO, USA) as a chemotactic agent in 200 mL DMEM (GIBCO, U S A.) supplemented with 1 mL/L BCS. AP-0, AP-1, AP-2 and AP-3 at a dose of 50 mL (7.0 mg/ml) were added into the Millicell. After the microplates and Millicells were incubated for 20 hours at 37 °C, 50 mL/L CO2 (Heraeus, Germany), each upper surface of membrane was scrubbed 3 times with a cotton swab. All of the membranes were fixed with 950 mL/L ethanol and then taken off for HE staining. HHCC cells infiltrated into the membrane were counted under a high power microscope. All experiments were performed in triplicate.
Inhibition of AP-0-AP-3 on HHCC adhesion to extracellular matrix proteins  Each well of the 96-well microplates was coated with FN and Matrigel, 2 mg for each one, respectively. The coated wells were allowed to dry, then 20 mL 10 g/L BSA was added into each well and incubated for 1 hour. The wells were washed with PBS. Each well containing 200 mL (2×105) HHCC and 50 mL (7.0 g/L) APs was incubated for 2 hours at 37 °C, 50 mL/L CO2. After each well was washed 3 times with 200 mL PBS, 40 mg MTT was added into each one and incubated for 4 hours at 37 °C, 50 mL/L CO2. Then the liquid was removed, and 200 mL DMSO was added into each well. The absorbance of each well was detected by a microplate Reader (Bio-Rad 450, USA) at 490 nm. Triplicate determinations were performed at each data point.
Influences of AP-0-AP-3 on HHCC chemotactic migration  The outer-surface of each Millicell was paved with 10 mg FN as a chemotactic agent. 150 mL (1.5×105) HHCC cells cultured in DMEM supplemented with 1 mL/L BCS, was added into each Millicell. Then the Millicells were cultured in 24-well microplates containing 200 mL DMEM supplemented with 1 mL/L BCS in each well. AP-0, AP-1, AP-2 and AP-3 at doses of 50 mL (7.0 g/L) were added into the Millicells respectively. After the microplates containing Millicells were incubated for 20 hours at 37 °C, 50 mL/L CO2, each upper surface of the membrane was scrubbed 3 times with a cotton swab. Then the membranes were fixed with 950 mL/L ethanol and taken off for HE staining. The HHCC cells infiltrated into the membrane were counted under a high power microscope. All experiments were performed in triplicate.

Statistical analysis
Differences of weights, cell counts and absorbance between the experimental and control groups were examined by using ANOVA (analysis of variance). Differences of life prolongation rates were examined by Cox proportional hazards regression.

RESULTS
Effects of Angelica polysaccharide (AP-0) on mice transplanted tumors
Influences of AP-0 on immunological organs of mice bearing S180  Although the differences of tumor’s weights between the three AP-0 groups and N.S. control group were not significant, thymus weights of mice receiving AP-0 were significantly lighter than those of mice treated by N.S. Whereas, thymus weights of mice receiving AP-0 were significantly heavier than those of mice treated by Cy (Table 1). Thymus weights of mice receiving doses of AP-0 at 100 mg/kg (P<0.05), 30 mg/kg and 300 mg/kg (P<0.01) were lighter than those of NS group. The thymus weights of mice receiving doses of dAP-0 at 30 mg/kg (P<0.05), 100 mg/kg and 300 mg/kg (P<0.01) were heavier than those of Cy group.

Table 1  Masses of body, tumor, thymus and spleen of mice bearing S180  10 days after being treated with AP-0, Cy and N S ( *)

Group Mice (n)(d10/d0) m (body)(g) m (tumor)(g) m (thymus)(mg) m (spleen)(g)
N S 10/10 253 2.6±0.8d 69±17 0.25±0.08d
Cy 9/9 193b 1.2±0.4 16±10b 0.06±0.02
AP-0          
30 mg/kg 9/10 225 2.8±1.0d 35±19bd 0.22±0.13d
100 mg/kg 8/10 223 2.7±0.5d 46±16ad 0.20±0.08d
300 mg/kg 7/10 222 3.0±1.3d 44±14bd 0.34±0.14d

aP<0.05, bP<0.01 vs N S, dP<0.01 vs Cy.

Effects of AP-0 on mice bearing EAC  The average weight of mice in each group receiving AP-0 treatment was far significantly lighter than that of NS group, suggesting that the amounts of ascitic fluid produced in the mice of experimental groups were less than those of NS groups (Table 2). The survival time of each AP-0 treated group was longer than that of NS group within 60 day observation. However, significant difference was found only between the AP-0 300 mg/kg treated group and NS group (Table 2).

Table 2  Survival and body masses of mice bearing EAC after being treated with AP-0

Group n Survival (days) Life prolongation rate (%) m (body)/(g) ( *)
d 0 d 10 
N S 10 14.1 0.0 19.9±0.9 42.2±1.9
5-FU 10 60.0 325.0 20.2±0.9 24.7±3.6b
AP-0
30 mg/kg 10 26.5 89.7 19.8±1.6 36.5±5.2b
100 mg/kg 10 18.4 30.5 19.4±1.2 35.8±3.0b
300 mg/kg 10 36.0 155.3a 19.3±1.0 31.3±3.8b

aP<0.05 vs N S, bP<0.001 vs N S.

Effects of AP-0 on mice bearing L1210  The survival time of mice receiving AP-0 at doses of 30 mg/kg and 100 mg/kg was longer than that of NS group within 30 day observation. Only 30 mg/kg group had a significant difference compared with N.S. group (Table 3). The effect was not dose-dependent.

Table 3  Survival of mice with L1210 after being treated with AP-0 ( *)

Group n Survival time (days) Life prolongation rate (%)
N S 0 15.0 0.0
Cy 5 30.0 200.0
AP-0
30 mg/kg-  1 25.0 66.7a
100 mg/kg 0 23.5 56.7
300 mg/kg 0 15.0 0.0

aP<0.05 vs N S.

Effects of Angelica polysaccharides on invasion and metastasis of hepatocellular carcinoma in vitro
Inhibition of AP-0-AP-3 on HHCC infiltrating into reconstituted basement membrane
  AP-0, AP-1, AP-2 and AP-3 could inhibit HHCC cells to infiltrate into the reconstituted basement membrane with inhibitory rates of 56.4 %, 38.6 %, 68.3 % and 26.7 %, respectively. Among them, AP-0 and AP-2 had significant inhibitory effects (P<0.05) compared with the control (Table 4).

Table 4  Inhibition of Angelica polysaccharides on infiltration and migration of HHCC

Group Infiltration Migration
Infiltrated cells ( *) Inhibitory rate(%) Migrated cells ( *) Inhibitory rate(%)
Control 20.2±18.5 0.0 23.6±18.7 0.0
AP-0 8.8±9.2a 56.4 29.5±17.8 \
AP-1 12.4±9.5 38.6 14.4±4.8 39. 0
AP-2 6.4±2.9a 68.3 17.0±7.9 28.0
AP-3 14.8±14.5 26.7 16.3±9.0 30.9

aP<0.05 vs Control.

Influences of AP-0-AP-3 on HHCC adhesion to extracellular matrix proteins  AP-0, AP-1, AP-2 and AP-3 could inhibit HHCC cells adhesion to Matrigel and FN by different degrees. However, only AP-3 could significantly inhibit adhesion of HHCC cells  to FN (Table 5).

Table 5  Influence of Angelica polysaccharides on adhesion of HHCC to Matrigel and fibronectin

Group Matrigel Fibronectin
A 490 nm( *) Inhibitory rate (%) A 490 nm( *) Inhibitory rate (%)
Control 0.131±0.029 0.0 0.099±0.023 0.0
AP-0 0.114±0.006 12.9 0.098±0.017 1.0
AP-1 0.118±0.037 9.9 0.082±0.004 17.2
AP-2 0.105±0.018 19.8 0.073±0.014 26.0
AP-3 0.098±0.020 25.2 0.069±0.008a 30.3

aP<0.05 vs Control.

Influences of AP-0-AP-3 on HHCC chemotactic migration abilities  AP-0 had no inhibitory effect on the migration of HHCC cells, but its sub-constituents AP-1, AP-2 and AP-3 had weak inhibitory effects on the migration of HHCC cells into membranes, with no statistical significance compared with N.S.group (P<0.05, Table 4).

DISCUSSION
Polysaccharides from various kinds of herbal medicines or plants have extensive pharmacological activities. Since Letinan, a polysaccharide from Lentinus edodes (Berk.) Sing (Chihara, et al. Nature. 1969;22:687-688) was discovered to inhibit mouse sarcoma 180, a lot of plant polysaccharides have been investigated into their anti-tumor effects and the related mechanisms (Chihara, et al, Nature. 1970;225:943-944; Maeda Y, et al. Nature.1971;229:634). In the present study, we examined systematically the anti-tumor effects of polysaccharides from Chinese Danggui (Angelica sinensis) in mice according to the criteria of anti-tumor drug evaluation. AP-0 might have no direct inhibition on murine solid tumor S180, but it could significantly decrease the weights of thymus of mice bearing S180. Gu et al (Bull Acad Mil Med Sci.1986;10:401) reported that two types of polysaccharides from Angelica could not only decrease the weights of thymus, but also decrease the amounts of peripheral T and B lymphocytes of normal and tumor-bearing mice. Maeda believed that the tumor-inhibiting effect of Lentinan was mediated by T lymphocytes. Our results of the S180 experiments suggested that AP-0 had significant influences on thymus of mice, but the effects were not strong enough to inhibit the growth of tumor. By using body-mass as an indicator of the amount of ascitic fluid produced in EAC-mice, we discovered that AP-0 inhibited the production of ascitic fluid and prolonged the survival of the mice. Kumazawa, et al (Immunology. 1982; 47:75) previously found that AIP, which was an immunostimulating polysaccharide separated from hot water extract of Angelica acutiloba Kitagawa (Yamato Tohki), prolonged the survival of mice bearing EAC. Likewise, AP-0 inhibited the production of ascitic fluid and prolonged the life of mice bearing L1210. The results of in vivo experiments suggested that AP-0 had obvious anti-tumor effects on murine ascitic tumors (AEC and L1210), and also affected the immune organ (thymus) of mice bearing S180. Immunostimulatory activities found in the polysaccharides from Panax ginseng, Spirulina platensis, Aphanizomenon flos-aquae and Chlorella pyrenoidosa also suggested that immuno-mediated effects might be the main mechanism of polysaccharides anti-tumor actions[23,24].  Polysaccharides with potent anti-tumor effects have been used clinically for cancer immunotherapy combined with radiotherapy and chemotherapy[25-27].
    Invasion and metastasis are essential characteristics of malignant tumors. Tumor invasion and metastasis are a multi-step process associated with multiple-factors, such as adhesion and migration of tumor cells, degradation of exracellular matrix (ECM), and angiogenesis[28]. Molecules existing in ECM and receptors or ligands existing on the surfaces of tumor cells played critical roles in invasion and metastasis[29,30]. Polysaccharides, such as proteoglycans and glycosaminoglycans are the main constituents of ECM. Liu et al[15] demonstrated that heparan sulfate glycosaminoglycan coat presenting on tumor cells contained bioactive sequences that impinged on tumor-cell growth and metastasis. Hyaluronan, an extracellular polysaccharide that has been implicated in tumor invasion, was one of the major constituents of stromal myxoid changes[16]. As to the polysaccharides from herbal medicines or plants, their anti-metastatic effects have been reported. Modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit, given orally, inhibited carbohydrate-mediated tumor growth, angiogenesis, and metastasis in vivo[17] . Protein-bound polysaccharide PSK inhibited tumor invasiveness by down-regulation of TGF-beta1, uPA, MMP-2 and MMP-9 expressed in two human tumor cell lines, pancreatic cancer cell line (NOR-P1) and gastric cancer cell line (MK-1P3) [18]. Enhancement of HLA class-I expression on tumor cells after PSK treatment might be one of the mechanisms responsible for the induction of anti-tumor immunity by PSK[19].
   The present anti-metastasis study employed human hepatocellular carcinoma cell (HHCC) co-cultured with fibroblast, a kind of important stromal cell, to test the inhibitory effects of AP-0, AP-1, AP-2 and AP-3 on metastasis in vitro. The results of our experiments showed that AP-0 and its sub-constituents could inhibit the infiltration, adhesion and migration of HHCC by different degrees. By analyzing the biological-effect and chemical-composition, we found that there might be some relationship between the anti-invasion activities and the uronic acids containing APs. AP-0 and AP-3 had the strongest anti-degradation effects on basement membrane, and also possessed the highest amounts of uronic acids of 210 g/kg and 257 g/kg among the 4 polysaccharides from Angelica. On the other hand, AP-3 with the lowest content of uronic acids had the most effective anti-adhesion action on HHCC cells to FN among the 4 polysaccharides. The polysaccharides rich in anion groups, such as heparin and heparan sulfate, are closely related to the action between cells and ECM. Based on this, it is proposed that AP rich in uronic acides act as analogues of natural polysaccharides in ECM, and exhibit their anti-metastasis effects.
     The findings in the present study suggest that polysaccharides from Angelica not only have anti-tumor effects on murine tumors of S180, EAC and L1210 in vivo, but also can inhibit invasion of HHCC in vitro.

REFERENCES
1    Hardy ML. Herbs of special interest to women. quiz 327-329. J Am Pharm Assoc (Wash) 2000; 40: 234-342
2    Bradley RR, Cunniff PJ, Pereira BJ, Jaber BL. Hematopoietic effect of Radix Angelica sinensis in a hemodialysis patient. 
      Am J Kidney Dis 1999; 34: 349-354
3    Cho CH, Mei QB, Shang P, Lee SS, So HL, Guo X, Li Y. Study of the gastrointestinal protective effects of 
      polysaccharides from Angelica sinensis in rats. Planta Med 2000; 66: 348-351
4    Ye YN, So HL, Liu ES, Shin VY, Cho CH. Effect of polysaccharides from Angelica sinensis on gastric ulcer healing. Life 
      Sci 2003; 72: 925-932
5    Ye YN, Liu ES, Shin VY, Koo MW, Li Y, Wei EQ, Matsui H, Cho CH. A mechanistic study of proliferation induced 
      by Angelica sinensis in a normal gastric epithelial cell line. Biochem Pharmacol 2001; 61: 1439-1448
6    Ye YN, Koo MW, Li Y, Matsui H, Cho CH. Angelica sinensis modulates migration and proliferation of gastric epithelial 
      cells. Life Sci 2001; 68: 961-968
7    Yang T, Jia M, Mei Q, Shang P. Effects of Angelica polysaccharide on blood coagulation and platelet aggregation. 
      Zhong Yao Cai 2002; 25: 344-345
8    Ye YN, Liu ES, Li Y, So HL, Cho CC, Sheng HP, Lee SS, Cho CH. Protective effect of polysaccharides-enriched fraction 
      from Angelica sinensis on hepatic injury. Life Sci 2001; 69: 637-646
9    Choy YM, Leung KN, Cho CS, Wong CK, Pang PK. Immunopharmacological studies of low molecular weight 
      polysaccharide from Angelica sinensis. Am J Chin Med 1994; 22: 137-145
10  Jiang SM, Xiao ZM, Xu ZH. Inhibitory activity of polysaccharide extracts from three kinds of edible fungi on proliferation 
      of human hepatoma SMMC-7721 cell and mouse implanted S180 tumor. World J Gastroenterol 1999; 5: 404-407
11  Chen Q, Yang GW, An LG. Apoptosis of hepatoma cells SMMC-7721 induced by Ginkgo biloba seed polysaccharide. 
      World J Gastroenterol 2002; 8: 832-836
12  Tang ZY. Hepatocellular carcinoma-cause, treatment and metastasis. World J Gastroenterol 2001; 7: 445-454
13  Korn WM. Moving toward an understanding of the metastatic proc ess in hepatocellular carcinoma. World J 
      Gastroentero 2001; 7: 777-778
14  Smorenburg SM, Van Noorden CJ. The complex effects of heparins on cancer progression and metastasis in 
      experimental studies. Pharmacol Rev 2001; 53: 93-105
15  Liu D, Shriver Z, Venkataraman G, El Shabrawi Y, Sasisekharan R. Tumor cell surface heparan sulfate as 
      cryptic promoters or inhibitors of tumor growth and metastasis. Proc Natl Acad Sci U S A 2002; 99: 568-573
16  Wernicke M, Pineiro LC, Caramutti D, Dorn VG, Raffo MM, Guixa HG, Telenta M, Morandi AA. Breast cancer stromal 
      myxoid changes are associated with tumor invasion and metastasis: a central role for hyaluronan. Mod Pathol 
      2003; 16: 99-107
17  Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, Raz A. Inhibition of human cancer cell growth 
      and metastasis in nude mice by oral intake of modified citrus pectin. J Natl Cancer Inst 2002; 94: 1854-1862
18  Zhang H, Morisaki T, Matsunaga H, Sato N, Uchiyama A, Hashizume K, Nagumo F, Tadano J, Katano M. Protein-
      bound polysaccharide PSK inhibits tumor invasiveness by down-regulation of TGF-beta1 and MMPs. Clin Exp 
      Metastasis 2000; 18: 343-352
19  Iguchi C, Nio Y, Takeda H, Yamasawa K, Hirahara N, Toga T, Itakura M, Tamura K. Plant polysaccharide PSK: 
      cytostatic effects on growth and invasion; modulating effect on the expression of HLA and adhesion molecules 
      on human gastric and colonic tumor cell surface. Anticancer Res 2001; 21: 1007-1013
20  Fisher M, Yang LX. Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer 
      immunotherapy. Anticancer Res 2002; 22: 1737-1754
21  Yamada H, Kiyohara H, Cyong JC, Kojima Y, Kumazawa Y, Otsuka Y. Studies on polysaccharides from Angelica 
      acutiloba. Part 1. Fractionation and biological properties of polysaccharides. Planta Med 1984; 50: 163-167
22  DeRoock IB, Pennington ME, Sroka TC, Lam KS, Boeden GT, Bair EL, Cress AE. Synthetic peptides inhibit adhension 
      of human tumor cells to extracellular matrix proteins. Cancer Res  2001; 61: 3308-3313
23  Shin JY, Song JY, Yun YS, Yang HO, Rhee DK, Pyo S.Immunostimulating effects of acidic polysaccharides extract of 
      Panax ginseng on macrophage function. Immunopharmacol Immunotoxicol 2002; 24: 469-482
24  Pugh N, Ross SA, ElSohly HN, ElSohly MA, Pasco DS. Isolation of three high molecular weight polysaccharide 
      preparations with potent immunostimulatory activity from Spirulina platensis, aphanizomenon flos-aquae and 
      Chlorella pyrenoidosa. Planta Med 2001; 67: 737-742
25  Xie FY, Zeng ZF, Huang HY. Clinical observation on nasopharyngeal carcinoma treated with combined therapy 
      of radiotherapy and ginseng polysaccharide injection. Zhongguo Zhongxiyi Jiehe Zazhi 2001; 21: 332-324
26  Yunmbam MK, Wellstein A. The bacterial polysaccharide tecogalan blocks growth of breast cancer cells in vivo. Oncol 
      Rep 2001; 8: 161-164
27  Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev 2000; 5: 4-27
28  Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Chen J, Gao DM,Bao WH. Establishment of cell clones with different 
      metastatic potential from the metastatic hepatoc ellular carcinoma cell line MHCC97. World J Gastroenterol 
      2001; 7: 630-636
29  Liu LX, Jiang HC, Liu ZH, Zhou J, Zhang WH, Zhu AL, Wang XQ, Wu M. Integrin gene expression profiles of 
      human hepatocellular carcinoma. World J Gastroenterol 2002; 8: 631-637
30  Su JM, Gui L, Zhou YP, Zha XL. Expression of focal adhesion kinase and a5 and b1 integrins in carcinomas and its 
      clinical significance. World J Gastroenterol 2002; 8: 613-618

   Edited by Zhu LH  

 

Reviews Add
more>>


Related Articles:
more>>