title: A rationale for the clinical development of the thymidylate synthase inhibitor ZD9331 in ovarian and other solid tumours.
abstract: 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<or=median. The four ovarian and one colon cell line that were relatively more sensitive to ZD9331 expressed FPGS mRNA<or=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.
authors.affiliation: The Section of Medicine, Institute of Cancer Research, 15 Cotswold Road, Belmont, Surrey, Sutton, UK. annj@icr.ac.uk
authors.forename: Ann L
authors.initials: AL
authors.lastname: Jackman
authors.forename: Camille J
authors.initials: CJ
authors.lastname: Melin
authors.forename: Rosemary
authors.initials: R
authors.lastname: Kimbell
authors.forename: Lisa
authors.initials: L
authors.lastname: Brunton
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
authors.forename: Davinder S
authors.initials: DS
authors.lastname: Theti
authors.forename: Mike
authors.initials: M
authors.lastname: Walton
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005493:Folic Acid Antagonists / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D010453:Peptide Synthases / Q000235:genetics; D011799:Quinazolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011799:Quinazolines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013876:Thiophenes; C094299:ZD 9331; D013940:Thymidylate Synthase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; C068874:raltitrexed