Antithymidylate resistance enables transgene selection and cell survival for T cells in the presence of 5-fluorouracil and antifolates

摘要: Antithymidylates (AThy) constitute a class of drugs used in the treatment cancers such as lung, colon, breast and pancreas. These inhibit DNA synthesis by targeting enzymes dihydrofolate reductase (DHFR) and/or thymidylate synthase (TYMS). AThys effectively cancer cells, also T preventing anticancer immunity, which might otherwise develop from AThy-induced destruction. We establish that cells expressing mutant DHFR--DHFR L22F, F31S (DHFR(FS))--and/or TYMS--TYMS T51S, G52S (TYMS(SS))-effectively survive toxic concentrations methotrexate, pemetrexed 5-fluorouracil. Furthermore, we show DHFR(FS) permitted rapid selection an inducible suicide transgene cells. findings demonstrate AThy resistances prevent cytotoxicity to while permitting important transgenes. This technological development could enhance vitro vivo survival T-cell therapeutics being designed for broad range cancers.