Molecularly evolved thymidylate synthase inhibits 5-fluorodeoxyuridine toxicity in human hematopoietic cells.
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.
Bielas
Jason H
JH
Molecular Diagnostics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. jbielas@fhcrc.org
Schmitt
Michael W
MW
Icreverzi
Amalia
A
Ericson
Nolan G
NG
Loeb
Lawrence A
LA
D019943:Amino Acid Substitution; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics*; D005467:Floxuridine / Q000009:adverse effects* / Q000627:therapeutic use; D015870:Gene Expression; D015316:Genetic Therapy; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D011487:Protein Conformation; D013489:Suppression, Genetic; D013940:Thymidylate Synthase / Q000737:chemistry / Q000235:genetics*; D014161:Transduction, Genetic
D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D013940:Thymidylate Synthase
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