In vitro discovery of promising anti-cancer drug combinations using iterative maximisation of a therapeutic index

Scientific Reports
M KashifM G Gustafsson


In vitro-based search for promising anti-cancer drug combinations may provide important leads to improved cancer therapies. Currently there are no integrated computational-experimental methods specifically designed to search for combinations, maximizing a predefined therapeutic index (TI) defined in terms of appropriate model systems. Here, such a pipeline is presented allowing the search for optimal combinations among an arbitrary number of drugs while also taking experimental variability into account. The TI optimized is the cytotoxicity difference (in vitro) between a target model and an adverse side effect model. Focusing on colorectal carcinoma (CRC), the pipeline provided several combinations that are effective in six different CRC models with limited cytotoxicity in normal cell models. Herein we describe the identification of the combination (Trichostatin A, Afungin, 17-AAG) and present results from subsequent characterisations, including efficacy in primary cultures of tumour cells from CRC patients. We hypothesize that its effect derives from potentiation of the proteotoxic action of 17-AAG by Trichostatin A and Afungin. The discovered drug combinations against CRC are significant findings themselves and also indicate ...Continue Reading


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Jul 12, 2014·International Journal of Biological Sciences·Zhiming Li, Wei-Guo Zhu

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Software Mentioned

BioScript Pro
ArrayScan VTI Reader
: Profiler
MACS ( Medicinal Algorithmic Combinatorial Screen )
Tool Command Language ( TCL )

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