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Antitumor antibiotic C-3509 as well as anti-tumor biochemical modulator Geldanamycin

Author: LiaoZhiYong
Tutor: ZhenYongSu;LouZhiXian;HuJiLan
School: Peking Union Medical College , China
Course: Microbial Pharmacy
Keywords: Chromophore Anti-cancer drugs Anti-tumor effects Research Progress Chaperone Antibiotic Biological activity Molecular targets Spermatogonia Anti-tumor substance
CLC: R979.1
Type: PhD thesis
Year: 2000
Downloads: 96
Quote: 0
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The goal of the study was set to search for antitumor antobiotic with extremely potent cytotoxicity against cancer cells. Using spermatogonial assay as prescreen to the antitumor compound and antibacterial assay to follow up the active principle during fermentation, isolation and purification, we obtained two parts of highly potent antitumor antibiotics, C-3509 (A) and (B), from a newly isolate identified as Micromonospora echinospora var Sheshansis. The main component in C-3509 (A) and (B) were about 70% and 85%, respectively. C-3509 (A) was a kind of brownish amorphous powder and C-3509 (B) was an off-white amorphous powder. Both of the highly active C-3509 (A) and (B) were soluble in CH2Cl2, ethyl acetate, acetone and the lower alcohols but practically insoluble in water. They were very sensitive to acids (pH < 2.0), bases (pH > 9.0), heat and light, but quite stable in CH2Cl2 and ethyl acetate. The fermentation broth of C-3509 was stable under the condition of low temperature of -20 °C and without light. According to the physico-chemical properties, especially the UV spectrum and MS of C-3509 (B), we proposed that C-3509 may be a member of enediyne antibiotics, similar to calicheamicins. Analyzed by agarose gel electrophoresis, the C-3509 (B) cleaved pBR322 DNA into pieces with different extent at the concentrations of 10 and 1.0 ug/ml and caused breakage in supercoiled DNA, inducing nicked DNA and linear DNA at the concentration of 0.1 μg/ml under basic condition. Treatment of HL-60 cells with 1.0 μg/ml of C-3509 (B) showed " comet " phenomenon by use of single cell gel electrophoresis. Measured by spermatogonial assay, it is positive for C-3509 (A) and (B) at the concentration of 10 and 1.0 ug/ml respectively. The IC50 values of CDDP, MMC and C-3509 (B) for hepatoma Bel-7402 cells were 1.00, 0.65, 0.00612 μg/ml, respectively by MTT assay. As for lung cancer PG cells, the IC50 values were 0.77, 0.89 and 0.013 μg/ml, respectively. By clonogenic assay, ADR, MMC, C-3509 (B) inhibited the clonogenic formation of Bel-7402 cells. In terms of inhibition of colony formation, the activity of C-3509 (B) was 580-fold and 240-fold more potent than that of ADR and MMC, respectively. In conclusion, C-3509 was an extremely potent antitumor

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