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Molecular characterisation of 2 cell-lines selected for resistance to the folate-based thymidylate synthase inhibitor, ZD1694

Lookup NU author(s): Professor Alan Calvert, Professor John LunecORCiD


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Resistance to anti-cancer drugs has proved to be a major barrier in the clinical management of neoplastic disease. We have investigated the mechanistic basis for resistance to folate-based thymidylate synthase (TS) inhibitors using two cell lines selected for resistance to ZD1694 (N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino] -2-thenoyl)-L-glutamic acid), a drug currently in phase III clinical trial, The degree of resistance was >20000 for the human lymphoblastoid cell line WIL2:R and approximately 14 for the ovarian carcinoma cell line CH1:R. In both cases resistance was associated with increased TS activity. The W1L2:R cell line had an approximately 100-fold increase in TS gene copy number and mRNA levels and a 500- to 1000-fold increase in enzyme levels determined using quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Southern and Western blotting. The CHI:R cell line had an approximately 2- to 2.5-fold increase in TS gene copy number, mRNA and protein levels. In both cell lines the fold resistance determined was significantly higher than the fold increase in target enzyme DNA, mRNA or protein levels. Small changes in TS levels may therefore translate to clinically significant alterations in drug sensitivity.

Publication metadata

Author(s): Freemantle, S. J., Jackman, A. L., Kelland, L. R., Calvert, A. H., Lunec, J.

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 1995

Volume: 71

Issue: 5

Pages: 925-930

Print publication date: 01/05/1995

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827