Chemoprevention by difluoromethylornithine: correlation of an in vitro human cell assay with human clinical data for biomarker modulation.
The efficacy of difluoromethylornithine (DFMO) as a chemopreventive agent has been tested in vitro using a human epidermal cell (HEC) assay with growth inhibition and involucrin induction as endpoints. Suppression of polyamine content is currently being utilized as a biomarker in clinical trials for the chemopreventive efficacy of DFMO against colon cancer formation. We have now examined the effects of DFMO on suppression of polyamine content in the HEC assay. The findings indicate 1) the % change in spermidine to spermine ratio and the depletion of putrescine show excellent correlation with chemopreventive efficacy in vitro; 2) the effective concentrations in vitro overlap the plasma concentrations in the clinical trial. These observations serve as further validation of the usefulness of the HEC assay as a screen for chemopreventive efficacy.
Elmore
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E
Department of Radiation Oncology and Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA 92697, USA.
Stringer
D E
DE
Steele
V E
VE
Gerner
E W
EW
Redpath
J L
JL
D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D018890:Chemoprevention; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002273:Carcinogens; D013876:Thiophenes; D013096:Spermine; C003218:1,3-propane sultone; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine