title: Gene expression profiles of colorectal carcinoma in response to neo-adjuvant chemotherapy.
abstract: The combination of irinotecan and a fluoropyrimidine has been widely accepted as a treatment for advanced colorectal carcinoma. However, there have been no evaluable data on the feasibility of these combinations. To assess the significance of such combinations, we attempted to identify gene expression patterns in response to irinotecan and two different types of fluoropyrimidines. In 12 patients dispositioned to receive preoperative chemotherapy for colorectal carcinoma, pre-therapy tumor biopsies and final resected specimens were available for analysis. Patients were randomly assigned to receive one of the following four regimens: (I), oral doxifluridine; (II), intravenous infusion of 5-FU; (III), intravenous infusion of irinotecan; (IV), combination of doxifluridine and irinotecan (I+III). To identify genes whose expressions changed, we analyzed the gene expression profiles prior to and after these therapies using an oligonucleotide microarray consisting of 12,000 genes. Next, we focused on the genes that demonstrated similar kinetics of altered expression in all patients in each of the regimens. We identified two proto-oncogenes, nuclear receptor of T-cells (NOT) and c-fos, that were up-regulated in doxifluridine- and irinotecan-related regimens but unchanged in the 5-FU-related regimen. Moreover, group IV tumors showed the highest apoptotic rate and lowest proliferation activity following the combined chemotherapy. These results suggest that doxifluridine has a synergistic impact on the therapeutic effect of irinotecan by up-regulating proto-oncogenes such as NOT and c-fos, and thus justify the use of one of the irinotecan and fluoropyrimidine combinations.
authors.affiliation: The Second Department of Surgery, Mie University School of Medicine, Tsu, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Inoue
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Shirane
authors.forename: Chikao
authors.initials: C
authors.lastname: Miki
authors.forename: Junichiro
authors.initials: J
authors.lastname: Hiro
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Minako
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Kazushige
authors.initials: K
authors.lastname: Mori
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yanagi
authors.forename: Masato
authors.initials: M
authors.lastname: Kusunoki
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D004347:Drug Interactions; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016762:Genes, fos; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D000077146:Irinotecan; D005472:Fluorouracil; C025034:doxifluridine; D002166:Camptothecin