title: Combination Efficacy of Astragalus membranaceus and Curcuma wenyujin at Different Stages of Tumor Progression in an Imageable Orthotopic Nude Mouse Model of Metastatic Human Ovarian Cancer Expressing Red Fluorescent Protein.
abstract: OBJECTIVE
  The present study determined the efficacy of extracts of Astragalus membranaceus (AM) and Curcuma wenyujin (CW), a traditional Chinese medicine herbal mixture, at different tumor stages of an orthotopic nude mouse model of human ovarian cancer expressing red fluorescent protein.
  
  
  METHODS
  The tumor-bearing mice were treated with cisplatinum (CDDP), AM, CW, or a combination of AM and CW in each of three tumor stages, using the same regimen. Group 1 received saline as negative control. Group 2 received CDDP i.p. as positive control with a dose of 2 mg/kg, every three days. Group 3 received AM daily via oral gavage, at a dose of 9120 mg/kg. Group 4 received CW daily via oral gavage, at a dose of 4560 mg/kg. Groups 5, 6 and 7 received combinations of AM and CW daily via oral gavage at low (AM, 2280 mg/kg; CW, 1140 mg/kg), medium (AM, 4560 mg/kg; CW 2280 mg/kg), and high (AM, 9120 mg/kg; CW, 4560 mg/kg) doses. The expression of angiogenesis- and apoptosis-related genes in the tumors were analyzed by immunohistochemistry for matrix metalloproteinase 2 (MMP-2), vascular endothelial growth factor (VEGF) fibroblast growth factor 2 (FGF-2), B-cell lymphoma 2 (Bcl-2) and cyclooxygenase 2 (Cox-2), and by polymerase chain reaction for MMP-2, FGF-2 and Bcl-2.
  
  
  RESULTS
  CDDP, AM, and its combination with CW-induced significant growth inhibition of Stage I tumors. Strong efficacy of the combination of AM and CW at high dose was observed. Monotherapy with CDDP, AM, CW, and the combination treatments did not significantly inhibit Stage II and III tumors. The expression of MMP-2, VEGF, FGF-2, and Cox-2 was significantly reduced in Stage I tumors treated with AM, CW, and their combination, suggesting a possible role of these angiogenesis- and apoptosis-related genes in the observed efficacy of the agents tested.
  
  
  CONCLUSIONS
  This study is the first report on the efficacy of anticancer agents at different stages of ovarian cancer in an orthotopic mouse model. As the tumor progressed, it became treatment-resistant, similar to the clinical situation, further demonstrating the utility of the model and the need for agents acrtive in advanced-stage ovarian cancer.
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Yin
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing, P.R. China talknow@njucm.edu.cn.
authors.forename: Decai
authors.initials: D
authors.lastname: Tang
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing, P.R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Dai
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing, P.R. China.
authors.forename: Mianhua
authors.initials: M
authors.lastname: Wu
authors.affiliation: Origin Biosciences Inc., Nanjing, Jiangsu, P.R. China.
authors.forename: Y U
authors.initials: YU
authors.lastname: Sun
authors.affiliation: Origin Biosciences Inc., Nanjing, Jiangsu, P.R. China AntiCancer, Inc., San Diego, CA, U.S.A.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Yang
authors.affiliation: AntiCancer, Inc., San Diego, CA, U.S.A. Department of Surgery, University of California, San Diego, CA, U.S.A.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing, P.R. China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Nanjing University of Chinese Medicine, Nanjing, P.R. China.
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Guo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D027885:Astragalus propinquus / Q000737:chemistry*; D045744:Cell Line, Tumor; D030024:Curcuma / Q000737:chemistry*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000097573:Red Fluorescent Protein
chemical_list: D051546:Cyclooxygenase 2; D004365:Drugs, Chinese Herbal; D016222:Fibroblast Growth Factor 2; D008164:Luminescent Proteins; D020778:Matrix Metalloproteinase 2; D042461:Vascular Endothelial Growth Factor A; D000097573:Red Fluorescent Protein; C496540:PTGS2 protein, human
keywords: Astragalus membranaceus; Curcuma wenyujin; metastasis; nude mice; orthotopic; ovarian cancer; red fluorescent protein; tumor progression