title: Expression of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, E2F-1, Bak, Bcl-X, and Bcl-2, and clinical outcomes for gastric cancer patients treated with bolus 5-fluorouracil.
abstract: Few studies have investigated the biological factors associated with sensitivity to bolus infusions of 5-fluorouracil (5FU), including sequential methotrexate (MTX)/5FU therapy. We investigated the relationship between the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), E2F-1, Bcl-2, Bak, and Bcl-X, and the chemotherapeutic effects of sequential MTX/5FU. We studied 38 patients with unresectable or recurrent gastric cancer, treated weekly with sequential MTX/5FU (MTX 100 mg/m2, 5FU 600 mg/m2, by bolus infusions, with a three-hour interval). Expression of the above proteins was examined in initial biopsy samples with immunohistochemical methods. Immunohistochemical reactivity was defined as positive when over 25% of cancer cells showed strong staining in the cytoplasm for TS, TP, DPD, Bak, Bcl-2, and Bcl-X, and in the nucleus for E2F-1. The overall response rate was 28% in the 29 patients who had measurable lesions. Bak-negative patients showed a higher response rate than Bak-positive patients (39% versus 9%, respectively; p=0.1096), although expression of the other proteins was not associated with chemosensitivity. The median survival time (MST) of all patients was 256 days. Bak-negative patients survived significantly longer than Bak-positive patients (MST, 302 days versus 134 days, respectively; p=0.0044). Bcl-X-negative patients survived significantly longer than Bcl-X-positive patients (MST, 302 days versus 215 days, respectively; p=0.0080). Furthermore, patients negative for both Bak and Bcl-X had significantly better prognoses than other patients (MST, 373 days; p<0.0001). Within the limits of the small patient population, multivariate analysis using the Cox proportional hazards model showed that Bak, Bcl-X, and histological type were independent variables predicting survival (p=0.0008, 0.0081, and 0.0082, respectively). Although previously described predictive markers for protracted infusion of 5FU, including TS, TP, and DPD, might not be associated with clinical outcome in patients treated with sequential MTX/5FU, Bak may be a useful marker for chemoresponse and survival. Furthermore, both Bcl-X expression and the coupled expression of Bak and Bcl-X, as well as histological type, may be useful predictive markers for survival.
authors.affiliation: Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital East (NCCHE), Chiba 277-8577, Japan. matahara@east.ncc.go.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Tahara
authors.forename: Atsuhi
authors.initials: A
authors.lastname: Ochiai
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tahara
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Yoshida
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D015999:Multivariate Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016019:Survival Analysis; D013939:Thymidine Phosphorylase / Q000096:biosynthesis; D013940:Thymidylate Synthase / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis; D016896:Treatment Outcome; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; D008727:Methotrexate