Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors.

Abstract

PURPOSE:

The predictive role of the quantification of thymidylate synthase (TS) in tumors treated with antifolate drugs, such as 5-fluorouracil (5-FU), has been extensively reported in a variety of human tumors. Neuroendocrine tumors (NET) represent potential targets of antifolate agents, but no data on TS expression level in these tumors are currently available.

EXPERIMENTAL DESIGN:

A series of 116 NETs were collected, including 58 gastroenteropancreatic (GEP) and 58 lung NETs. In 24 well-differentiated GEP neuroendocrine carcinomas (WD-NEC), a 5-FU-based treatment was given. Total RNA was extracted from microdissected paraffin blocks. TS mRNA quantification was done by real-time PCR, whereas protein expression was evaluated by immunohistochemistry.

RESULTS:

By means of both quantification by real-time PCR and immunohistochemistry, a higher TS expression in pulmonary small cell lung cancer and large cell NEC compared with typical and atypical carcinoids was observed (P < 0.01). Similarly, in GEP tumors, a higher TS expression in poorly differentiated carcinomas than both WD-NEC and benign tumors (P < 0.01) was found. In patients with WD-NEC treated with 5-FU, high TS mRNA levels were associated with shorter time to progression (P = 0.002) and overall survival (P = 0.04). This negative prognostic role was confirmed in multivariate analysis adjusting for major prognostic variables (P = 0.01). No association between TS mRNA and survival was observed in WD-NEC patients not receiving 5-FU.

CONCLUSIONS:

This study, for the first time, (a) reports the differential TS expression in the spectrum of NETs and (b) indicates TS as a possible predictive marker of treatment efficacy in WD-NEC patients treated with 5-FU.

• Authors: Paolo Ceppi, Marco Volante, Anna Ferrero, Luisella Righi, Ida Rapa, Rosj Rosas, Alfredo Berruti, Luigi Dogliotti, Giorgio V Scagliotti, Mauro Papotti
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 4 Pg. 1059-64 (Feb 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18281538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• RNA, Messenger
• Thymidylate Synthase
• Fluorouracil

Topics

• Antineoplastic Agents (therapeutic use)
• Digestive System Neoplasms (drug therapy, enzymology, mortality)
• Drug Resistance, Neoplasm (physiology)
• Fluorouracil (therapeutic use)
• Gene Expression
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy, enzymology)
• Neuroendocrine Tumors (drug therapy, enzymology, mortality)
• RNA, Messenger (analysis)
• Reverse Transcriptase Polymerase Chain Reaction
• Thymidylate Synthase (biosynthesis)