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dc.contributor.authorAherne, W
dc.contributor.authorJackman, A
dc.date.accessioned2018-06-05T09:21:35Z
dc.date.issued2002-07-18
dc.identifierhttp://publications.icr.ac.uk/1184/
dc.identifier.citationBIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2002, 1587 (2-3), pp. 215 - 223
dc.identifier.issn0925-4439
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1705
dc.description.abstractA rationale for the clinical development of the thymidylate synthase inhibitor ZD9331 in ovarian and other solid tumours. ZD9331 is an antifolate drug that potently and specifically inhibits thymidylate synthase (TS). In contrast with TS inhibitors such as raltitrexed, it cannot be polyglutamated, leading to antitumour activity independent of folylpolyglutamyl synthetase (FPGS) activity. The growth inhibition IC50 values for ZD9331 and raltitrexed were determined for a panel of 18 human tumour cell lines, that included six colon and six ovarian. The colon lines largely displayed overlapping sensitivities to both drugs with only one of the six lines being drug resistant. In contrast, the ovarian cell lines displayed non-overlapping sensitivities with four being highly resistant to raltitrexed and only one was cross-resistant to ZD9331. Studies were undertaken to explain these results. The colon and ovarian cell lines were characterised for TS activity, and TS and FPGS mRNA expression. TS activity correlated with sensitivity to ZD9331 (r=0.50;p=0.097) and raltitrexed (r=0.74;p=0.0063). Provided the data from the highly drug-resistant cell lines (BE and 41 M) were omitted, TS mRNA expression levels also correlated with ZD9331 (r=0.77; p=0.013) and raltitrexed IC50 (r=0.84; p=0.0031). FPGS mRNA expression correlated with higher sensitivity to raltitrexed relative to ZD9331 (higher ZD9331/raltitrexed IC50 ratios) (r=0.62; p=0.048). Similarly, cell lines with IC50 ratios>median expressed a 1.8-fold higher median level of FPGS mRNA (p=0.0087) compared with those with ratios less than or equal to median. The four ovarian and one colon cell line that were relatively more sensitive to ZD9331 expressed FPGS mRNA less than or equal to median (p=0.061). Thus, ZD9331 overcomes resistance to raltitrexed in ovarian tumour cell lines expressing low levels of FPGS. These data, and others demonstrating a lack of cross-resistance between cisplatin and ZD9331, support the clinical evaluation of ZD9331 in platinum- refractory ovarian cancer.
dc.format.extent215 - 223
dc.languageeng
dc.language.isoeng
dc.subjectCARCINOMA CELL-LINES; DIHYDROPYRIMIDINE DEHYDROGENASE; ACQUIRED-RESISTANCE; PLATINUM COMPLEXES; HUMAN LEUKEMIA; MESSENGER-RNA; CANCER; EXPRESSION; SENSITIVITY; SYNTHETASE ZD9331; raltitrexed; thymidylate synthase; folylpolyglutamyl synthetase; ovarian cancer
dc.titleA rationale for the clinical development of the thymidylate synthase inhibitor ZD9331 in ovarian and other solid tumours
dc.typeJournal Article
rioxxterms.licenseref.startdate2002-07-18
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
pubs.issue2-3
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.volume1587en_US
pubs.embargo.termsNot known
icr.researchteamTarget Evaluation and Molecular Therapeuticsen_US
dc.contributor.icrauthorWalton, Michaelen


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