Open AccessDeveloping an in silico model of the modulation of base excision repair using methoxyamine for more targeted cancer therapeutics
Author(s) -
GurkanCavusoglu Evren,
Avadhani Sriya,
Liu Lili,
Kinsella Timothy J.,
Loparo Kenneth A.
Publication year - 2013
Publication title -
iet systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.367
H-Index - 50
eISSN - 1751-8857
pISSN - 1751-8849
DOI - 10.1049/iet-syb.2011.0045
Subject(s) - base excision repair , cytotoxicity , dna repair , in silico , cancer research , dna damage , computational biology , chemistry , biology , dna , biochemistry , in vitro , gene
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.