Cap-dependent translation blockade and fixed dose-rate gemcitabine: interaction in an in vitro bioreactor system.
Translation initiation commences with the binding of eIF-4F to the mRNA 5'-end cap. eIF-4F binds the cap structure via its eIF-4E subunit, which is the rate-limiting step for the initiation of translation. This pathway can be inhibited by 4E-binding proteins (4E-BPs). The present study investigated prolonged gemcitabine infusion in combination with reduced eIF-4E function on NSCLC cell viability in an in vitro bioreactor system. To assess attachment to the hollow fibers, cells with dominant active 4E-BP1 were first analyzed by scanning electron microscopy. Cells were treated with 0.5- or 2.5h (fixed dose rate) infusion (same total dose), simulating human plasma gemcitabine concentration-time profiles. An interaction was observed between fixed dose rate infusion gemcitabine and presence of dominant active 4E-BP1. We conclude that cap-dependent translation blockade and fixed dose rate infusion gemcitabine treatment results in a significant interaction affecting cell viability in vitro.
Department of Experimental and Clinical Pharmacology, College of Pharmacy and Comprehensive Cancer Center, University of Minnesota, 717 Delaware St. SE, Minneapolis, MN 55414, USA.
Brent W
BW
Williams
Jessica J
JJ
Chang
Ruth M
RM
Chi
Paul H
PH
Marker
Chris D
CD
Frethem
Chap T
CT
Le
Robert A
RA
Kratzke
Mark N
MN
Kirstein
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D019149:Bioreactors; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008854:Microscopy, Electron; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D039561:Eukaryotic Initiation Factor-4E; D012333:RNA, Messenger; D003841:Deoxycytidine; D000093542:Gemcitabine