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

Publication Type:

Journal Article

Source:

Human gene therapy, Volume 20, Issue 12, p.1703-7 (2009)

Keywords:

2009, Amino Acid Substitution, Antimetabolites, Antineoplastic, Center-Authored Paper, Drug Resistance, Floxuridine, gene expression, Gene Therapy, Hematopoietic Stem Cells, Humans, Protein Conformation, Public Health Sciences Division, Suppression, Genetic, thymidylate synthase, Transduction, Genetic

Abstract:

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.