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.
Williams
Brent W
BW
Department of Experimental and Clinical Pharmacology, College of Pharmacy and Comprehensive Cancer Center, University of Minnesota, 717 Delaware St. SE, Minneapolis, MN 55414, USA.
Chang
Jessica J
JJ
Chi
Ruth M
RM
Marker
Paul H
PH
Frethem
Chris D
CD
Le
Chap T
CT
Kratzke
Robert A
RA
Kirstein
Mark N
MN
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