title: Transmission of apoptosis in human colorectal tumor cells exposed to capecitabine, Xeloda, is mediated via Fas.
abstract: We developed an original in vitro model dedicated to the exploration of molecular pharmacology of the new oral fluoropyrimidine capecitabine (Xeloda). More specifically, in this report, we investigated whether apoptosis induced by capecitabine was mediated by the Fas/FasL system. To achieve this goal, a specific in vitro coculture model mixing hepatoma and human colorectal cell line was used. A bystander effect was observed between HepG2 and LS174T cells treated with capecitabine. Besides this, Xeloda showed a 7-fold higher cytotoxicity and markedly stronger apoptotic potential in thymidine phosphorylase (TP)-transfected LS174T-c2 cells. The striking enhancement of thymidylate synthase inhibition that we observed in cells with high TP activity was most probably at the origin of the potentiation of capecitabine antiproliferative efficacy. In addition, this increase of sensitivity was accompanied by a strong overexpression of the CD95-Fas receptor on the cell surface. Both Fas and FasL mRNA expression were triggered after exposing TP+ cells to the drug. This implication of Fas in Xeloda-induced apoptosis was next confirmed by using antagonistic anti-Fas and anti-FasL antibodies that proved to reverse capecitabine antiproliferative activity, thus highlighting the key role that Fas could play in the optimization of an antitumor response to fluoropyrimidine drugs. Our data, therefore, show that TP plays a key role in the capecitabine activity and that the Fas/FasL system could be considered as a new determinant for Xeloda efficacy.
authors.affiliation: Laboratoire de Toxicocinétique et Pharmacocinétique, Faculté de Pharmacie, 27, Boulevard Jean Moulin, 13385 Marseille, France. joseph.ciccolini@pharmacie.univ-mrs.fr
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fina
authors.forename: Karine
authors.initials: K
authors.lastname: Bezulier
authors.forename: Sarah
authors.initials: S
authors.lastname: Giacometti
authors.forename: Magali
authors.initials: M
authors.lastname: Roussel
authors.forename: Alexandre
authors.initials: A
authors.lastname: Evrard
authors.forename: Pierre
authors.initials: P
authors.lastname: Cuq
authors.forename: Sylvie
authors.initials: S
authors.lastname: Romain
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Martin
authors.forename: Claude
authors.initials: C
authors.lastname: Aubert
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D024201:Bystander Effect; D000069287:Capecitabine; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor; D003841:Deoxycytidine; D000069287:Capecitabine; D013940:Thymidylate Synthase; D005472:Fluorouracil