Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism
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Muhammad Kashif1,3, Claes Andersson1, Sharmineh Mansoori1, Rolf Larsson1, Peter Nygren2 and Mats G. Gustafsson1
1Department of Medical Sciences, Cancer Pharmacology, and Computational Medicine, Uppsala University Academic Hospital, Uppsala, Sweden
2Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
3Current/Present address: Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
Mats G. Gustafsson, email: [email protected]
Keywords: synergy analysis; combinations; iso-genic; COMBIA; R package
Received: March 13, 2017 Accepted: September 03, 2017 Published: October 19, 2017
We analyzed survival effects for 15 different pairs of clinically relevant anti-cancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair.
COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergyTM II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing.
In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line.
In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism.
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