title: Developing an in silico model of the modulation of base excision repair using methoxyamine for more targeted cancer therapeutics.
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.
authors.affiliation: Department of Electrical Engineering and Computer Science, School of Engineering, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-7071, USA. exg44@case.edu
authors.forename: Evren
authors.initials: E
authors.lastname: Gurkan-Cavusoglu
authors.forename: Sriya
authors.initials: S
authors.lastname: Avadhani
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kinsella
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Loparo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D003198:Computer Simulation; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics* / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000235:genetics*; D015195:Drug Design; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D006801:Humans; D006898:Hydroxylamines / Q000008:administration & dosage*; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006898:Hydroxylamines; C005214:methoxyamine