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Letters in Drug Design & Discovery 9 (9): 815-822 (2012-11)

Fichtner I.; Cinatl J.; Michaelis M.; Sanders L.C.; Hilger R.; Kennedy B.N.; Reynolds A.L.; Hackenberg F.; Lally G.; Quinn S.J.; McRae I.; Tacke M.

In vitro and in vivo investigations into the carbene silver acetate anticancer drug candidate SBC1

Description:
The anticancer drug candidate (1-methyl-3-(p-cyanobenzyl)benzimidazole-2-ylidene)silver(I)acetate (SBC1) was tested in vitro against human neuroblastoma cells, UKF-NB-3 and UKF-NB-6, delivering IC50 values of 29 +/- 5 and 29 +/- 4 μM, while further testing against cisplatin-, carboplatin- and oxaliplatin-resistant UKF-NB-3/6 sub-lines showed no cross-resistance with respect to SBC1. A similar trend was found for SBC1 against the human colon carcinoma cell line HCT8 with an IC50 value of 3.1 +/- 0.9 {Mu}M; SBC1 was again able to break cisplatin- and carboplatin-resistance in the corresponding sub-lines. SBC1 was also tested against the prostate cancer cell line PC-3 and its paclitaxel-resistant sub-line, which gave IC50 values of 14.1 +/- 0.9 and 14.5 +/- 0.8 {Mu}M, which indicated no cross-resistance with paclitaxel. In order to test the possible transport of SBC1 via albumin the binding of SBC1 against this transport protein was measured using a fluorescence titration, which gave an {Delta}G value of 28 +/- 3 kJ/mol. In circular dichroism and DNA denaturation assays SBC1 proved to be a strongly DNA-binding drug candidate. SBC1 was then given at 25 and 50 mg/kg/d, in four injections to two cohorts of eight CAKI-1 tumor-bearing NMRI:nu/nu mice, while a further cohort was treated with solvent only. At these two dosages SBC1 showed a borderline toxicity leading to mortality and body weight loss, while no significant tumor growth reduction or influence on blood parameter with respect to the solvent-treated control group was observed. Further in vivo testing against zebrafish larvae revealed significant toxicity of SBC1 at micromolar concentrations; no useable anti-angiogenic dosage was observed.

Keywords: Zebrafish, Mice, Animals, Zebrafish Intersegmental Vessel Assay, Xenograft Mouse Model, DNA-Binding Assay, Albumin-Binding Assay, Renal Cell Cancer, Carbene-Silver Complex, Anti-Angiogenic Drug, Anticancer Drug

Type: Article

Official URL: https://doi.org/10.2174/157018012803307987
MDC Repository: https://edoc.mdc-berlin.de/12723/