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The relationship between intrinsic thymidylate synthase expression and sensitivity to THYMITAQ (TM) in human leukaemia and colorectal carcinoma cell lines

Estlin, EJ; Balmanno, K; Calvert, AH; Hall, AG; Lunec, J; Newell, DR; Pearson, ADJ; (1997) The relationship between intrinsic thymidylate synthase expression and sensitivity to THYMITAQ (TM) in human leukaemia and colorectal carcinoma cell lines. BRIT J CANCER , 76 (12) 1579 - 1585.

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Abstract

Thymidylate synthase (TS) expression has been characterized for a panel of eight human colorectal carcinoma and five human leukaemia cell lines, to relate differences in intrinsic TS activity, protein and mRNA levels to growth inhibition caused by continuous exposure to THYMITAQ(TM), a specific non-classical antifolate TS inhibitor. Although a 20-fold variation in sensitivity to THYMITAQ(TM) was found within the colorectal cell line panel (IC50 0.12-2.7 mu M), sensitivity was not related to TS activity, TS protein or TS mRNA levels. For the leukaemic cell lines, only a twofold range in sensitivity to THYMITAQ(TM) was observed (IC50 0.87-2.3 mu M), and this did not correlate with TS activity, TS protein or TS mRNA levels. Across all of the cell lines, TS activity was linearly related to TS protein levels (r(2) = 0.87, P < 0.0001). However, for both the colorectal and leukaemia cell line panels, no relationship was found between TS mRNA/18S rRNA ratios and either TS activity or TS protein, consistent with the importance of post-transcriptional mechanisms in regulating TS activity. Two of the colorectal cell lines (BE and HCT116) and one of the human leukaemic cell lines (HL60), were intrinsically resistant to THYMITAQ(TM) (IC50 > 2 mu M) in the absence of TS overexpression, suggesting that, subsequent to TS inhibition, events such as DNA repair and tolerance to apoptotic stimuli are also important determinants of sensitivity to THYMITAQ(TM).

Type: Article
Title: The relationship between intrinsic thymidylate synthase expression and sensitivity to THYMITAQ (TM) in human leukaemia and colorectal carcinoma cell lines
Keywords: thymidylate synthase, THYMITAQ (TM), human colorectal carcinoma, human leukaemia, cell lines, ACQUIRED-RESISTANCE, ANTICANCER DRUGS, MESSENGER-RNA, INHIBITORS, 5-FLUORO-2'-DEOXYURIDINE, 5-FLUOROURACIL, CANCER, MECHANISMS, ZD1694, TUMORS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/351824
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