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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

Mechanisms of resistance to fluoropyrimidines

Z G Zhang1, A Harstrick, Y M Rustum

  • 1Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263.

Seminars in Oncology
|April 1, 1992
PubMed

Insights

Acquired resistance to fluoropyrimidines like 5-FU can occur through increased thymidylate synthase or deficient thymidine kinase. Understanding these mechanisms is key to overcoming drug resistance in cancer treatment.

Area of Science:

  • Biochemistry
  • Oncology
  • Pharmacology

Background:

  • Fluoropyrimidines, including fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd), are vital in treating various cancers.
  • Acquired resistance to these drugs is a significant clinical challenge, limiting their long-term efficacy.

Purpose of the Study:

  • To investigate the biochemical basis of acquired resistance to fluoropyrimidines in cancer cell lines.
  • To identify specific molecular mechanisms contributing to resistance against 5-FU and FdUrd.

Main Methods:

  • Development of resistant cell lines: MCF7/Adr (breast cancer) selected for Adriamycin resistance and Fd9XR (colon cancer) selected for FdUrd resistance.
  • Biochemical analysis of resistant cell lines, focusing on enzyme levels (thymidylate synthase, thymidine kinase), drug metabolism, and uptake.

Main Results:

  • MCF7/Adr cells exhibited a 25-fold resistance to 5-FU and 67-fold to FdUrd, with significantly elevated thymidylate synthase levels.
  • Fd9XR cells showed 1,000-fold resistance to FdUrd but not 5-FU, due to a deficiency in thymidine kinase, preventing FdUrd activation.
  • Key biochemical factors like folate pools, drug uptake, metabolism, and retention remained unchanged in resistant cells.

Conclusions:

  • Acquired resistance to fluoropyrimidines can manifest through distinct biochemical pathways, including overexpression of the target enzyme or impaired drug activation.
  • Identifying these specific resistance mechanisms is crucial for developing strategies to circumvent drug resistance and improve cancer therapy.

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