A 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

Does breakfast-club attendance affect schoolchildren's nutrient intake? A study of dietary intake at three schools.

Lack of breakfast has been implicated as a factor contributing to children's poor diets and school performance. Breakfast-club schemes, where children are provided with breakfast in school at the start of the school day, have been initiated by the Department of Health in schools throughout England, UK. The aim of the present study was to compare the energy and nutrient intakes of schoolchildren who attended breakfast clubs (attendee subjects) with those who did not (control subjects). Three different schools were studied, involving a total of 111 children aged between 9 and 15 years. There were fifty-nine attendee and fifty-two control subjects. The two groups were matched for eligibility for school meals. All subjects completed a 3 d weighed food diary for estimation of nutrient intake. Height and weight were measured and BMI calculated. Nutrient intake data were analysed using a general linear model with age as a covariate. The demographic and anthropometric characteristics of the attendee and control subjects were similar. Children who attended breakfast clubs had significantly greater intakes of fat (% energy), saturated fat (% energy) and Na than control subjects. Thus, in these schools breakfast-club participation was not associated with superior nutrient intake or improvements in dietary pattern.