Developing an in silico model of the modulation of base excision repair using methoxyamine for more targeted cancer therapeutics. Issue 2 (1st April 2013)

• Record Type: Journal Article
• Authors: Gurkan‐Cavusoglu, Evren; Avadhani, Sriya; Liu, Lili; Kinsella, Timothy J.; Loparo, Kenneth A.
• Is Part Of: IET systems biology. Volume 7:Issue 2(2013)
• Page Start: 27
• Page End: 37
• Publication Date: 2013-04-01
• Subjects: biochemistry -- biomedical materials -- cancer -- DNA -- enzymes -- molecular biophysics -- radiation therapy -- toxicology; in silico model -- base excision repair modulation -- methoxyamine -- targeted cancer therapeutics -- DNA repair pathway -- exogenous nonbulky base damage processing -- cancer chemotherapy drugs -- ionising radiation -- small molecule chemical inhibitor -- IR cytotoxicity -- human cancers -- MX inhibitory effect -- BER pathway kinetics -- computational model -- repair pathway -- variable efficiency groups -- protein concentrations -- Latin hypercube sampling -- clustered simulation -- low efficiency repair groups -- high efficiency BER -- high efficiency repair groups -- medium efficiency repair groups; biochemistry -- biomedical materials -- cancer -- DNA -- enzymes -- molecular biophysics -- radiation therapy -- toxicology; in silico model -- base excision repair modulation -- methoxyamine -- targeted cancer therapeutics -- DNA repair pathway -- exogenous nonbulky base damage processing -- cancer chemotherapy drugs -- ionising radiation -- small molecule chemical inhibitor -- IR cytotoxicity -- human cancers -- MX inhibitory effect -- BER pathway kinetics -- computational model -- repair pathway -- variable efficiency groups -- protein concentrations -- Latin hypercube sampling -- clustered simulation -- low efficiency repair groups -- high efficiency BER -- high efficiency repair groups -- medium efficiency repair groups; Systems biology -- Periodicals; Cell physiology -- Periodicals; Biological systems -- Mathematical models -- Periodicals; Genetics -- Mathematical models -- Periodicals; Computational biology -- Periodicals; 573
• DOI: 10.1049/iet-syb.2011.0045
• Languages: English
• ISSNs: 1751-8849

Abstract

Abstract : Base excision repair (BER) is a major DNA repair pathway involved in the processing of exogenous non‐bulky base damages from certain classes of cancer chemotherapy drugs as well as ionising radiation (IR). Methoxyamine (MX) is a small molecule chemical inhibitor of BER that is shown to enhance chemotherapy and/or IR cytotoxicity in human cancers. In this study, the authors have analysed the inhibitory effect of MX on the BER pathway kinetics using a computational model of the repair pathway. The inhibitory effect of MX depends on the BER efficiency. The authors have generated variable efficiency groups using different sets of protein concentrations generated by Latin hypercube sampling, and they have clustered simulation results into high, medium and low efficiency repair groups. From analysis of the inhibitory effect of MX on each of the three groups, it is found that the inhibition is most effective for high efficiency BER, and least effective for low efficiency repair.