Antithymidylate resistance enables transgene selection and cell survival for T cells in the presence of 5-fluorouracil and antifolates.
Antithymidylates (AThy) constitute a class of drugs used in the treatment of cancers such as lung, colon, breast and pancreas. These drugs inhibit DNA synthesis by targeting the enzymes dihydrofolate reductase (DHFR) and/or thymidylate synthase (TYMS). AThys effectively inhibit cancer cells, and also inhibit T cells, preventing anticancer immunity, which might otherwise develop from AThy-induced cancer destruction. We establish that T cells expressing mutant DHFR--DHFR L22F, F31S (DHFR(FS))--and/or mutant TYMS--TYMS T51S, G52S (TYMS(SS))-effectively survive in toxic concentrations of AThys methotrexate, pemetrexed and 5-fluorouracil. Furthermore, we show that DHFR(FS) permitted rapid selection of an inducible suicide transgene in T cells. These findings demonstrate that AThy resistances prevent AThy cytotoxicity to T cells while permitting selection of important transgenes. This technological development could enhance in vitro and in vivo survival and selection of T-cell therapeutics being designed for a broad range of cancers.
Division of Pediatrics, Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center, Unit 907, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
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Rushworth
The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
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Alpert
The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.|University of Puerto Rico School of Medicine, San Juan, Puerto Rico, United States Minor Outlying Islands.
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Santana-Carrero
Division of Pediatrics, Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center, Unit 907, Houston, TX, USA.
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Olivares
Bellicum Pharmaceuticals, Houston, TX, USA.
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Spencer
Division of Pediatrics, Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center, Unit 907, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
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LJ
Cooper
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000235:genetics; D004351:Drug Resistance; D005472:Fluorouracil / Q000494:pharmacology* / Q000633:toxicity; D005493:Folic Acid Antagonists; D006801:Humans; D019169:Jurkat Cells; D008727:Methotrexate / Q000494:pharmacology* / Q000633:toxicity; D000068437:Pemetrexed / Q000494:pharmacology* / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D000068437:Pemetrexed; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D005472:Fluorouracil; D008727:Methotrexate