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Comparison of Pretherapeutic and Posttherapeutic Expression Levels of Chemotherapy-Associated Genes in Adenocarcinomas of the Esophagus Treated by 5-Fluorouracil– and Cisplatin-Based Neoadjuvant Chemotherapy

Rupert Langer MD, Katja Specht MD, Karen Becker MD, Philipp Ewald MD, Katja Ott MD, PhD, Florian Lordick MD, Jörg-Rüdiger Siewert MD, PhD, Heinz Höfler MD, PhD
DOI: http://dx.doi.org/10.1309/1U6X4L9XFJLJV940 191-197 First published online: 1 August 2007

Abstract

We analyzed expression of genes associated with metabolism of chemotherapeutic drugs in locally advanced esophageal adenocarcinomas before and after neoadjuvant chemotherapy to study whether there is a change in gene expression induced by chemotherapy and whether such changes are associated with tumor response or nonresponse. We included 21 patients with locally advanced esophageal adenocarcinomas treated by cisplatin- and 5-fluorouracil (5-FU)–based neoadjuvant chemotherapy before surgery. Messenger RNA was extracted from formalin-fixed, paraffinembedded preoperative endoscopic esophageal tumor biopsy specimens and tumor tissue specimens after surgical resection. Expression levels of chemotherapy metabolism–associated genes thymidylate synthase (TYMS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), methylenetetrahydrofolate reductase (MTHFR), multidrug resistance–associated protein 1 (MRP1), and multidrug-resistance gene 1 (MDR1 ) were determined by quantitative real-time reverse transcriptase– polymerase chain reaction.

There was a significant posttherapeutic reduction in the expression levels of TP (P = .028) and MRP1 (P = .006). Furthermore, down-regulation of MRP1 (P = .041) and TYMS(P = .028) after chemotherapy was associated with tumor response to chemotherapy, assessed clinically and by histopathologic tumor regression. Downregulation of chemotherapy metabolism–associated genes occurs after neoadjuvant chemotherapy and may modulate tumor response to chemotherapy.

Key Words:
  • Chemotherapy
  • Gene expression
  • Adenocarcinoma
  • Esophagus