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.

The Role of α-Folate Receptor-Mediated Transport in the Antitumor Activity of Antifolate Drugs

“…The sensitivity of the A431 cells to the antifolates in a physiological folate concentration (20 nM LV) ranged from 3 nM IC 50 (raltitrexed) to 90 nM IC 50 (ZD9331; Table 2) and is similar to that reported for other non-␣-FR-overexpressing tumor cell lines grown in standard commercial media (47). The results were similar in low folate conditions (1 nM LV), except that MTX was 8-fold more active (Table 2).…”

“…Response rates (Phase II) were ϳ10% in refractory disease, including some heavily pretreated patients (a complete response was seen in a patient receiving 8 th line therapy), but the ␣-FR expression status of the tumors is not known. Raltitrexed displayed similar activity in ovarian cancer, although low folylpolyglutamate synthetase expression in ovarian tumors may be a factor contributing to this low response rate (47,58). The activity of raltitrexed and pemetrexed in mesothelioma has been speculated to be attributable, at least in part, to ␣-FR-mediated uptake (42).…”

Fluorine in medicinal chemistry: A review of anti-cancer agents

“…Historically, methotrexate 16 has been an extremely useful and widely prescribed TS inhibitor but it is limited by its toxicity and appears to cause more damage to the cell genome than it gains from inhibition [26]. Gallagher and coworker [27] and Jackson et al [28] have recently reported phase II/III results indicating that the fluorinated analogue of methotrexate, ZD9331, 17 is active against ovarian cancer cell lines that are resistant to classical TS inhibitors and comparable to gemcitabine in the treatment of pancreatic cancer.…”

Bacterially-Derived Nanocells for Tumor-Targeted Delivery of Chemotherapeutics and Cell Cycle Inhibitors

“…Thymidylate synthase (TS) inhibitors form another class of new targeted drugs in development. [75][76][77][78] This effort has been necessary since first-line cytotoxic drugs for metastatic colorectal cancer such as 5-Fluorouracil, which is a TS inhibitor, 79 suffers from drawbacks of severe toxicity and rapid development of drug resistance. TS expression has been reported to be cell cycle dependent 80,81 and its activity levels are higher in proliferating cells than in non-proliferating cells.…”