Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy.
FOLFOX is a cytostatic drug combination for adjuvant treatment of colorectal cancer (CRC) consisting of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin. The mechanism of synergistic interaction of these drugs is poorly understood and little is known concerning the role of drug transporters and the impact of oxaliplatin metabolites oxalate and dichloro-diaminocyclohexane platinum. We therefore investigated the influence of FOLFOX components on drug transporter expression by quantitative real-time polymerase chain reaction and on the efficacy of each FOLFOX component by proliferation assay in the CRC model cell line LS180. Control experiments with transporter over-expressing cell lines were used to assess the significance of important transporters for the cytostatic activity of FOLFOX components. Moreover, we assessed the pharmacological contribution of the oxalato-ligand to the effect of oxaliplatin. FOLFOX components led to several alterations in expression of drug transporters. For instance, 5-FU significantly suppressed ATP7B and human organic cation transporter 2 and increased multidrug resistance-associated protein (MRP) 2 mRNA expression (5.8-fold). This was accompanied by a significant sensitisation to oxaliplatin. Over-expression of certain ABC-transporters (BCRP/ABCG2, MRP2/ABCC2 or MRP3/ABCC3) was demonstrated to be beneficial for the efficacy of oxaliplatin. The results obtained indicate that both down- and up-regulations of drug transporters could favour synergistic action of this drug combination. Moreover, oxaliplatin metabolite oxalate seems to positively modulate oxaliplatin's action as elucidated by median effect analysis. In conclusion, we propose as one mechanism for FOLFOX synergism the 5-FU mediated suppression of ATP7B, the over-expression of glutathione exporters such as MRP2/ABCC2 and the decrease of glutathione levels by oxalate.
Theile
Dirk
D
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Grebhardt
Sina
S
Haefeli
Walter Emil
WE
Weiss
Johanna
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000111:Acetylcysteine / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000494:pharmacology; D000077150:Oxaliplatin; D012333:RNA, Messenger / Q000096:biosynthesis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000111:Acetylcysteine; D000251:Adenosine Triphosphatases; D027682:Cation Transport Proteins; D005472:Fluorouracil; D005978:Glutathione; D002955:Leucovorin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012333:RNA, Messenger; C000715087:ABCC2 protein, human