Sepantronium Bromide (YM155)

443, 29

PC-3 s.c. (orthotopic) xenografts in male nude mice (BALB/c nu/nu)

YM155 is currently in Phase II clinical trial in advanced non-small cell lung carcinoma.

5 mg/kg

0.54 nM [1], 0.54 nM [1], 0.54 nM [1], 0.54 nM [1], 0.54 nM [1], 0.54 nM [1]

YM155 completely inhibits the tumor growth of PC-3 s.c. xenografted prostate tumors at doses of 3 and 10 mg/kg, without body weight loss and blood cell count decrease. Pharmacokinetic analysis shows that YM155 is highly distributed to tumor tissue. Moreover, YM155 shows 80% TGI at a dose of 5 mg/kg in PC-3 orthotopic xenografts. [1] The combination therapy with YM155 and gamma-radiation shows great antitumor activity against H460 or Calu6 xenografts in nude mice. [2]

Promoter-luciferase reporter assay, A 2, 767-bp sequence of human survivin gene promoter is isolated from human genomic DNA by PCR using Pyrobest polymerase and the following primers: 5'-GCGCGCTCGAGTCTAGACATGCGGATATATTC-3' and 5'-GCGCGAA-GCTTTGGCGGTTAATGGCGCGC-3'. The resulting PCR fragment is digested with XhoI/HindIII and ligated into the XhoI/HindIII cleavage site of the pGL3-Basic vector. The resulting plasmid is named pSUR-luc. DNA sequencing is done on all amplified sequences by a DNA sequencer. The activity of pSUR-luc is confirmed by luciferase assay with transiently transfected HeLa-S3 cells. Luciferase assay is done. The pGL3 control vector, which contains the SV40 promoter and enhancer sequences, is used. HeLa cells are stably transfected with pSUR-luc and pSV2bsr by Lipofect-AMINE 2000. After blasticidin selection at 10 ug/mL, a single colony is chosen based on appropriate luciferase signals and genetic stability over time and named HeLa-SURP-luc. CHO cells are stably transfected with pGL3-control and pSV2bsr. After blasticidin selection at 10 ug/mL, a single colony is chosen based on appropriate luciferase signals and genetic stability over time and named CHO-SV40-luc. Stocked cells from the HeLa-SURP-luc and CHO-SV40-luc clones are used for chemical screening and characterization of YM155. YM155 in DMSO are added to the cells, which had been seeded the previous day on 96-well plastic plates at 5, 103 per well. Luciferase activity is measured 24 hours later. IC50 is calculated by logistic analysis.

DMSO 55 mg/mL, Water 89 mg/mL, Ethanol 6 mg/mL

1H-Naphth[2, 3-d]imidazolium, 4, 9-dihydro-1-(2-methoxyethyl)-2-methyl-4, 9-dioxo-3-(2-pyrazinylmethyl)-, bromide (1:1)