title: Genomic profiling in CEPH cell lines distinguishes between the camptothecins and indenoisoquinolines.
abstract: We have attempted to use a familial genetics strategy to study mechanisms of topoisomerase 1 (Top1) inhibition. Investigations have steadily been chipping away at the pathways involved in cellular response following Top1 inhibition for more than 20 years. Our system-wide approach, which phenotypes a collection of genotyped human cell lines for sensitivity to compounds and interrogates all genes and molecular pathways simultaneously. Previously, we characterized the in vitro sensitivity of 15 families of Centre d'Etude Polymorphisme Humain (CEPH) cell lines (n = 142) to 9 camptothecin analogues. Linkage analysis revealed a pattern of 7 quantitative trait loci (QTL) shared by all of the camptothecins. To identify which, if any, QTLs are related to the general mechanism of Top1 inhibition or should be considered camptothecin specific, we characterized the in vitro sensitivity of the same panel of CEPH cell lines to the indenisoquinolones, a structurally distinct class of Top1 inhibitors. Four QTLs on chromosomes 1, 5, 11, and 16 were shared by both the camptothecins and the indenoisoquinolines and are considered associated with the general mechanism of Top1 inhibition. The remaining 3 QTLs (chromosomes 6 and 20) are considered specific to camptothecin-induced cytotoxicity. Finally, 8 QTLs were identified, which were unique to the indenoisoquinolines.
authors.affiliation: UNC Institute for Pharmacogenomics and Individualized Therapy, Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Venita Gresham
authors.initials: VG
authors.lastname: Watson
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hardison
authors.forename: Tyndall
authors.initials: T
authors.lastname: Harris
authors.forename: Alison
authors.initials: A
authors.lastname: Motsinger-Reif
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D040641:Quantitative Trait Loci; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin