title: Multidrug-resistant cancer cells facilitate E1-independent adenoviral replication: impact for cancer gene therapy.
abstract: Resistance to chemotherapy is responsible for a failure of current treatment regimens in cancer patients. We have reported previously that the Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug resistant-tumor phenotype. YB-1 predicts drug resistance and patient outcome in breast cancer. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In drug-resistant cancer cells and in adenovirus-infected cells YB-1 is found in the nucleus. Nuclear accumulation of YB-1 in adenovirus-infected cells is a function of the E1 region, and we have shown that YB-1 facilitates adenovirus replication. Here we report that E1A-deleted or mutant adenovirus vectors, such as Ad312 and Ad520, replicate efficiently in multidrug-resistant (MDR) cancer cells and induce an adenovirus cytopathic effect resulting in host cell lysis. Thus, replication-defective adenoviruses are a previously unrecognized vector system for a selective elimination of MDR cancer cells. Our work forms the basis for the development of novel oncolytic adenovirus vectors for the treatment of MDR malignant diseases in the clinical setting.
authors.affiliation: Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Klinikum Rechts der Isar, München, Germany. per.s.holm@lrz.tum.de
authors.forename: Per S
authors.initials: PS
authors.lastname: Holm
authors.forename: Hermann
authors.initials: H
authors.lastname: Lage
authors.forename: Stephan
authors.initials: S
authors.lastname: Bergmann
authors.forename: Karsten
authors.initials: K
authors.lastname: Jürchott
authors.forename: Gabriel
authors.initials: G
authors.lastname: Glockzin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bernshausen
authors.forename: Klaus
authors.initials: K
authors.lastname: Mantwill
authors.forename: Axel
authors.initials: A
authors.lastname: Ladhoff
authors.forename: Anke
authors.initials: A
authors.lastname: Wichert
authors.forename: Joe S
authors.initials: JS
authors.lastname: Mymryk
authors.forename: Thomas
authors.initials: T
authors.lastname: Ritter
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.forename: Bernd
authors.initials: B
authors.lastname: Gänsbacher
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Royer
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000260:Adenoviruses, Human / Q000235:genetics / Q000302:isolation & purification; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D018432:Drug Resistance, Multiple; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D014162:Transfection / Q000379:methods; D014779:Virus Replication / Q000235:genetics*
chemical_list: D017500:Adenovirus E1A Proteins; D017931:DNA Primers; D018076:DNA, Complementary