Effect of Thymidine Phosphorylase Gene Demethylation on Sensitivity to 5-Fluorouracil in Colorectal Cancer Cells

Anticancer Res. 2022 Feb;42(2):837-844. doi: 10.21873/anticanres.15541.

Abstract

Background/aim: Chemotherapy is used for recurrent and metastatic colorectal cancer, but the response rate of 5-fluorouracil (5-FU), the standard treatment for colorectal cancer, is low. We hypothesized that thymidine phosphorylase (TYMP) expression, a rate-limiting activating enzyme of 5-FU, is regulated by methylation of the gene promoter region, and demethylation of TYMP would increase sensitivity to 5-FU.

Materials and methods: HCT116 colon cancer cells were treated with 5-aza-2'-deoxycytidine, a demethylating agent, and changes in TYMP transcription and sensitivity to 5-FU were evaluated.

Results: TYMP expression increased over 54-fold in HCT116 transfected with TYMP. The cytotoxicity of 5-FU increased up to 5.5-fold. In comparison, in HCT116 treated with 5-aza-2'-deoxycytidine, TYMP expression increased 5.8-fold. However, the cytotoxicity of 5-FU remained unchanged.

Conclusion: Demethylating agent alone did not promote the cytotoxicity of 5-FU against colorectal cancer. To further increase the sensitivity to 5-FU, combination with adjuvant therapy focusing on metabolic pathways other than the TYMP pathway appear necessary.

Keywords: 5-fluorouracil; Colorectal cancer; inhibitor of methylation; thymidine phosphorylase.

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology*
  • Antimetabolites, Antineoplastic / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Decitabine / pharmacology
  • Demethylation
  • Drug Resistance, Neoplasm / drug effects
  • Fluorouracil / pharmacology*
  • Fluorouracil / therapeutic use
  • Humans
  • Thymidine Phosphorylase / genetics
  • Thymidine Phosphorylase / metabolism*
  • Transcription, Genetic

Substances

  • Antimetabolites, Antineoplastic
  • Decitabine
  • TYMP protein, human
  • Thymidine Phosphorylase
  • Fluorouracil