BGC 945 is a cyclopenta [g]quinazoline-based, thymidylate synthase inhibitor specifically transported into A-folate receptor (A-FR)-overexpressing tumors. Affinity of BGC 945 for the A-FR is 70% of the high-affinity ligand folic acid. In contrast to conventional antifolates, BGC 945 has low affinity for the widely expressed reduced-folate carrier (RFC). The K i for isolated thymidylate synthase is 1.2 nmol/L and the IC 50 for inhibition of the growth of A-FR-negative mouse L1210 or human A431 cells is f7 Mmol/L. In contrast, BGC 945 is highly potent in a range of A-FR-overexpressing human tumor cell lines (IC 50 f1-300 nmol/L). Pharmacokinetic variables measured following i.v. injection of 100 mg/kg BGC 945 to KB tumor-bearing mice showed rapid plasma clearance (0.021 L/h) and tissue distribution. The terminal half-lives in plasma, liver, kidney, spleen, and tumor were 2, 0.6, 5, 21, and 28 hours, respectively. Tumor BGC 945 concentration at 24 hours was f1 nmol/g tissue, at least 10-fold higher than that in plasma or normal tissues. Inhibition of thymidylate synthase in tissues leads to increased incorporation of 5-[125 I]-iodo-2V -deoxyuridine ([ 125 I]dUrd) into DNA. Forty-eight hours after injection of 100 mg/kg 6RS-BGC 945 ([ 125 I]dUrd injected at 24 hours), tumor was the only tissue with incorporation above control level (6-fold). The RFC-mediated thymidylate synthase inhibitor plevitrexed also increased uptake of [125 I]dUrd in tumor (10-fold) but, in contrast, also caused increased incorporation in other normal tissues such as spleen and small bowel (4.5-and 4.6-fold, respectively). These data suggest that BGC 945 selectively inhibits thymidylate synthase in A-FR-overexpressing tumors and should cause minimal toxicity to humans at therapeutic doses. (Cancer Res 2005; 65(24): 11721-8)

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Conclusions: Antifolate drugs, particularly ZD9331, have the potential for increased efficacy in tumors that highly overexpress the ␣-FR.

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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

The efficacy of pegfilgrastim±chemotherapy for mobilizing stem cells in patients with solid tumours was assessed. In cycle 0, a 14-day prechemotherapy cycle, patients (N ¼ 61) were randomized open-label to single doses of pegfilgrastim (6, 12 or 18 mg) on day 1, or daily filgrastim (10 lg/kg) for p7 days. Mean peak peripheral CD34 þ cell counts increased with pegfilgrastim dose, but were significantly higher than filgrastim only at the 18 mg dose (10.17 vs 4.96 Â 10 4 /ml; P ¼ 0.014). In the clinically relevant period of days 3-7, both 12 and 18 mg pegfilgrastim doses produced significantly higher peak CD34 þ counts (8.18 and 9.96 vs 4.51 Â 10 4 /ml for filgrastim; P ¼ 0.034 and 0.006). In cycle 1, patients received carboplatin/paclitaxel on day 1, followed from day 2 by pegfilgrastim 6-18 mg or daily filgrastim (5 lg/ kg/day for p14 days) as per randomization in cycle 0. There were no significant differences in mean peak CD34 þ count between pegfilgrastim and filgrastim, but there was an advantage for pegfilgrastim 18 mg in the relevant period of days 7-12 (3.14 vs 1.19 Â 10 4 /ml; P ¼ 0.043). A single pegfilgrastim dose (X6 mg) could be substituted for daily filgrastim in cytokine-only peripheral CD34 þ cell mobilization.

Pulmonary hypertension (PHT) is frequent in patients receiving hemodialysis (HD) and carries a high mortality. While it has been suggested that arteriovenous fistulae (AVF) may exacerbate PHT in HD patients, it has also been observed that creating AVF in patients with chronic lung disease and normal renal function may lead to improved exercise tolerance. Most of the observations regarding HD patients using echocardiography demonstrated that temporary closure of AVF improved pulmonary pressures. We present the case of a 45‐year‐old patient with chronic obstructive pulmonary disease on HD who experienced respiratory failure following AVF formation and underwent right heart catheterization. Severe PHT was diagnosed but transient occlusion of the fistula failed to improve the PHT. This case supports the theory that fistula creation does not exacerbate pre‐existing PHT and that AVF can be the access of choice in patients with known chronic lung disease and pulmonary hypertension.

BackgroundReal world data (RWD) are increasingly used to inform drug reimbursement decisions, but it is unclear how well outcomes from real world studies compare to those of clinical trials. This systematic review seeks to compare outcomes for sunitinib in routine UK clinical practice with the sunitinib registrational and expanded-access program clinical trials.MethodSystematic review of the real world published literature was undertaken. UK observational studies recording first- or second-line sunitinib efficacy were included. A qualitative summary of the results and comparison to the controlled clinical trials was conducted. Fifteen real world studies were included, 14 of which were only available as posters/presentations.ResultsReal world study reporting quality was generally low, making comparisons with the clinical trials difficult. Practice relating to starting dose, dose modification, timing of therapy initiation, and other factors varied between centers. Median progression-free survival and adverse events were generally comparable to the clinical trial outcomes, but overall survival was not.ConclusionThere are few published data on sunitinib use in UK clinical practice. Studies are characterized by lack of peer reviewed publication and heterogeneity in design, reporting, and analysis. For use of RWD in the reimbursement setting, data collection and reporting will need to improve.HighlightsThere are few published data on sunitinib use in UK clinical practice.Studies are characterized by lack of peer reviewed publication and heterogeneity in design, reporting, and analysis.Practice varies considerably between different UK centers.Median progression-free survival and adverse events are generally comparable to the clinical trial outcomes, but overall survival is not.For use of real world data in the reimbursement setting, data collection and reporting will need to improve.