title: Modulation of Cytotoxicity by Transcription-Coupled Nucleotide Excision Repair Is Independent of the Requirement for Bioactivation of Acylfulvene.
abstract: Bioactivation as well as DNA repair affects the susceptibility of cancer cells to the action of DNA-alkylating chemotherapeutic drugs. However, information is limited with regard to the relative contributions of these processes to the biological outcome of metabolically activated DNA alkylating agents. We evaluated the influence of cellular bioactivation capacity and DNA repair on cytotoxicity of the DNA alkylating agent acylfulvene (AF). We compared the cytotoxicity and RNA synthesis inhibition by AF and its synthetic activated analogue iso-M0 in a panel of fibroblast cell lines with deficiencies in transcription-coupled (TC-NER) or global genome nucleotide excision repair (GG-NER). We related these data to the inherent bioactivation capacity of each cell type on the basis of mRNA levels. We demonstrated that specific inactivation of TC-NER by siRNA had the largest positive impact on AF activity in a cancer cell line. These findings establish that transcription-coupled DNA repair reduces cellular sensitivity to AF, independent of the requirement for bioactivation.
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich , 8092 Zurich, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Otto
authors.affiliation: Department of Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Graciela
authors.initials: G
authors.lastname: Spivak
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich , 8092 Zurich, Switzerland.
authors.forename: Claudia M N
authors.initials: CM
authors.lastname: Aloisi
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich , 8057 Zurich, Switzerland.
authors.forename: Mirco
authors.initials: M
authors.lastname: Menigatti
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse , 8057 Zurich, Switzerland.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Naegeli
authors.affiliation: Department of Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Hanawalt
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich , 8092 Zurich, Switzerland.|Department of Chemistry, Michigan Technological University , Houghton, Michigan 49932, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: Tanasova
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich , 8092 Zurich, Switzerland.
authors.forename: Shana J
authors.identifier: 0000-0001-6808-5950
authors.initials: SJ
authors.lastname: Sturla
mesh_terms: D065767:Activation, Metabolic; D002460:Cell Line; D004260:DNA Repair; D006801:Humans; D012717:Sesquiterpenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D013141:Spiro Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D012717:Sesquiterpenes; D013141:Spiro Compounds; C079422:acylfulvene