title: Thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase expression, and histological tumour regression after 5-FU-based neo-adjuvant chemoradiotherapy in rectal cancer.
abstract: Pre-operative 5-fluorouracil (5-FU)-based chemoradiotherapy in locally advanced rectal cancer (UICC-II/III) may significantly reduce local tumour mass. Response to pre-operative treatment, however, varies significantly. Thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are thought to be important predictors for the efficiency of 5-FU-based treatment. The aim of this study was to determine the correlation between TS-, TP-, and DPD-gene expression and the response to 5-FU-based long-term pre-operative chemoradiotherapy assessed by histopathological tumour regression. Additionally, the predictive value of intra-tumoural TS-, TP-, and DPD-gene expression in pre-operative rectal tumour biopsies was assessed by correlation with the histopathological regression grade. Formalin-fixed, paraffin wax-embedded pre-operative biopsies (n = 14) and surgical resection specimens (n = 40) from patients with rectal carcinoma (clinical UICC stage II/III) receiving neo-adjuvant 5-FU-based chemoradiotherapy were studied for TS-, TP-, and DPD-gene expression by quantitative TaqMan real-time PCR after laser microdissection. Results were compared with standardized histopathological tumour regression analysis. There was a significant association between low TS-gene expression in pre-operative tumour biopsies and tumour response (p = 0.02). TS- and TP-gene expression was significantly lower in resection specimens of responders than of non-responders (p = 0.02) when microdissection was used. Statistical significance was even higher when TS and TP were combined (p = 0.0001). For the DPD gene, no significance was found at all. In conclusion, this study shows that TS gene expression in a pretreatment biopsy predicts the response of local rectal cancer to neo-adjuvant 5-FU-based chemoradiotherapy in a high percentage. Moreover, intra-tumoural TS- and TP-gene expression in surgical rectal specimens after neo-adjuvant chemoradiotherapy correlates significantly with histopathological tumour regression when microdissection is applied.
authors.affiliation: Institute for Pathology, University of Technology, Fetscherstrasse 74, D-01307 Dresden, Germany. Christiane.Jakob@uniklinikum-dresden.de
authors.forename: Christiane
authors.initials: C
authors.lastname: Jakob
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Aust
authors.forename: Wolfdietrich
authors.initials: W
authors.lastname: Meyer
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Baretton
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schwabe
authors.forename: Peter
authors.initials: P
authors.lastname: Häusler
authors.forename: Heinz
authors.initials: H
authors.lastname: Becker
authors.forename: Torsten
authors.initials: T
authors.lastname: Liersch
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000032:analysis* / Q000627:therapeutic use; D003131:Combined Modality Therapy / Q000379:methods; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis* / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011300:Preoperative Care / Q000379:methods; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D013939:Thymidine Phosphorylase / Q000032:analysis* / Q000235:genetics; D013940:Thymidylate Synthase / Q000032:analysis* / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil