PMID: 7537519May 1, 1995Paper

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

British Journal of Cancer
S E FreemantleJ Lunec

Abstract

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 > 20,000 for the human lymphoblastoid cell line W1L2: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 CH1: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 sign...Continue Reading

Citations

Oct 25, 2003·Oncogene·Rongbao Zhao, I David Goldman
Mar 3, 2007·Cancer Metastasis Reviews·Yehuda G Assaraf
Apr 27, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·A NaganumaS Kuge
Mar 29, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Maja J A de JongeJaap Verweij
Jun 27, 2002·Biochimica Et Biophysica Acta·G J PetersH M Pinedo

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