Molecularly evolved thymidylate synthase inhibits 5-fluorodeoxyuridine toxicity in human hematopoietic cells

Hum Gene Ther. 2009 Dec;20(12):1703-7. doi: 10.1089/hum.2009.053.


Thymidylate synthase (TS) inhibitors, such as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine (5-FUdR), are amongst the most frequently used chemotherapeutic drugs available, although their efficacy is often limited by myelotoxicity. An emerging strategy for overcoming bone marrow toxicity involves ex vivo genetic transfer of drug resistance to autologous hematopoietic progenitor cells, followed by reimplantation of the transfected cells before chemotherapy. Here we establish that expression of mutant TS genes, selected from millions of engineered variants, renders human hematopoietic cells resistant to 5-FUdR, and identify the most efficacious variant for gene therapeutic rescue of drug-induced myelosuppression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / therapeutic use
  • Drug Resistance / genetics*
  • Floxuridine / adverse effects*
  • Floxuridine / therapeutic use
  • Gene Expression
  • Genetic Therapy
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Protein Conformation
  • Suppression, Genetic
  • Thymidylate Synthase / chemistry
  • Thymidylate Synthase / genetics*
  • Transduction, Genetic*


  • Antimetabolites, Antineoplastic
  • Floxuridine
  • Thymidylate Synthase