Multidrug-resistant cancer cells facilitate E1-independent adenoviral replication: impact for cancer gene therapy.
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.
Holm
Per S
PS
Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Klinikum Rechts der Isar, München, Germany. per.s.holm@lrz.tum.de
Lage
Hermann
H
Bergmann
Stephan
S
Jürchott
Karsten
K
Glockzin
Gabriel
G
Bernshausen
Alexandra
A
Mantwill
Klaus
K
Ladhoff
Axel
A
Wichert
Anke
A
Mymryk
Joe S
JS
Ritter
Thomas
T
Dietel
Manfred
M
Gänsbacher
Bernd
B
Royer
Hans-Dieter
HD
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*
D017500:Adenovirus E1A Proteins; D017931:DNA Primers; D018076:DNA, Complementary