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The impact of p53 status on cellular sensitivity to antifolate drugs

X Lu1, J Errington, N J Curtin

  • 1Cancer Research Unit, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, United Kingdom.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 13, 2001
PubMed

Insights

p53 status impacts cellular sensitivity to antifolate drugs like Alimta and raltitrexed. Functional p53 may confer resistance, but this effect depends on cell background and assay methods, with non-functional p53 cells showing unbalanced growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The tumor suppressor protein p53 plays a critical role in cellular response to DNA damage and stress.
  • Antifolate drugs are widely used in cancer chemotherapy, targeting folate metabolism essential for DNA synthesis.
  • Understanding the interplay between p53 status and antifolate drug sensitivity is crucial for optimizing cancer treatment strategies.

Purpose of the Study:

  • To investigate the influence of p53 functional status on the sensitivity of human cancer cell lines to various antifolate drugs.
  • To explore potential mechanisms underlying differential drug responses in cells with and without functional p53.

Main Methods:

  • Utilized seven human cancer cell lines and their p53 non-functional counterparts.
  • Assessed p53 status through sequencing and functional assays.
  • Determined cellular sensitivity to Alimta, methotrexate, raltitrexed, and lometrexol using growth inhibition (sulphorhodamine B) and cytotoxicity (clonogenic) assays.
  • Analyzed cell cycle distribution, cell number, apoptosis, and protein content.

Main Results:

  • No clear correlation between p53 status and sensitivity to methotrexate or lometrexol.
  • Functional p53 was associated with potential resistance to Alimta and raltitrexed in some cell lines.
  • In specific paired cell lines (HCT-116 and A2780), functional p53 correlated with increased sensitivity to Alimta and raltitrexed.
  • Cells lacking functional p53 exhibited higher protein content post-treatment, indicating unbalanced cell growth.

Conclusions:

  • The impact of p53 status on antifolate drug sensitivity is complex and context-dependent.
  • Phenotypic/genotypic background and the chosen assay significantly influence observed drug responses.
  • Cells with non-functional p53 may exhibit altered growth dynamics, maintaining protein synthesis without cell division under antifolate treatment.

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