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Biological activity of the multitargeted antifolate, MTA (LY231514), in human cell lines with different resistance

R M Schultz1, V J Chen, J R Bewley

  • 1Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

Seminars in Oncology
|December 22, 1999
PubMed

Insights

This study reveals mechanisms of resistance to MTA in cancer cells, showing that resistance is multifactorial and stable. It highlights that secondary targets emerge beyond thymidylate synthase modulation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Methotrexate analog (MTA) requires polyglutamation for cytotoxicity.
  • MTA polyglutamates inhibit key folate metabolism enzymes like thymidylate synthase (TS).

Purpose of the Study:

  • Investigate the mechanistic basis of MTA resistance in human tumor cell lines.
  • Characterize the cellular changes and resistance patterns associated with MTA exposure.

Main Methods:

  • Developed MTA-resistant cell lines through stepwise increases in MTA concentration over 5 months.
  • Assessed cross-resistance to other antifolates (raltitrexed, methotrexate, LY309887).
  • Evaluated the protective effects of thymidine and hypoxanthine on MTA cytotoxicity.

Main Results:

  • Achieved significant MTA resistance (72- to 729-fold) in leukemia, colon, and ileocecal carcinoma cell lines.
  • Observed strong cross-resistance to raltitrexed but modest resistance to methotrexate and LY309887.
  • Identified distinct resistance patterns: GARFT-like (GC3MTA) and dihydrofolate reductase-like (HCT-8MTA, CCRF-CEM(MTA)).
  • GC3MTA cells showed increased TS activity; all resistant lines had reduced MTA accumulation.
  • Cells resistant to TS-targeting drugs showed less MTA resistance.

Conclusions:

  • MTA resistance is multifactorial, stable, and involves mechanisms beyond TS modulation.
  • Secondary targets and altered folate metabolism pathways contribute to MTA resistance.
  • Understanding these mechanisms is crucial for optimizing antifolate cancer therapy.

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