Efficacy and tolerability of the thymidylate synthase (TS) inhibitor, BGC 945 is mediated through its selective uptake via the α-folate receptor (α-FR) in IGROV-1 human tumor xenografts
Authors: Chau Ng, Melanie Valenti, Fraser Mitchell, Martin Forster, Davinder Theti, John Schurig, Suzanne Eccles, Ann Jackman
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3289 

BGC 945 is a tumor-targeted folate-based TS inhibitor in preclinical development (Gibbs et al, Cancer Res., 2005). Targeting is achieved by its unique selectivity for α-FR-mediated rather than reduced-folate carrier (RFC)-mediated uptake into cells. In contrast to the ubiquitous expression of the RFC in normal and malignant tissues, α-FR expression is over-expressed in many epithelial tumors but in most normal tissues is confined to the apical membrane surface inaccessible to circulating drugs. The sensitivity of human tumor cell lines to BGC 945 is dependent on α-FR expression levels and the GI50 can be as low as 3nM in highly overexpressing human tumor cells such as KB. Studies using pharmacodynamic (PD) markers of TS inhibition have demonstrated tumor selectivity of BGC 945 in mice bearing KB xenografts at doses ranging from 5-100mg/kg. This level of activity is explained by the slow clearance of BGC 945 from tumor (t1/2β=28h). The frequency and level of α-FR overexpression is particularly high in human ovarian tumors (~90% of cases) and we have therefore studied the effect of BGC 945 in IGROV-1 ovarian carcinoma xenografts. Expression levels are ~25% of those seen in KB cells (~23pmol folic acid (FA) binding sites/107 cells). α-FR-mediated TS and growth inhibition was demonstrated in vitro at BGC 945 concentrations as low as 30nM. Plasma and tumor deoxyuridine (dUrd) levels are PD endpoints of TS inhibition in proliferating normal tissues and tumor respectively. BGC 945 at 100mg/kg induced a 5-20-fold increase in tumor dUrd at 4-72h without increases in the plasma, consistent with tumor targeting. 200mg/kg BGC 945 induced only a small, transient increase in plasma dUrd at 4h consistent with some non-FR mediated TS inhibition when plasma drug levels were high. This dose is therefore predicted not to cause cytotoxicity to normal proliferating tissues and therefore was chosen for evaluating IGROV-1 antitumor activity. Mice have ~100-fold higher plasma thymidine levels than humans, which attenuates the activity of TS inhibitors. Chronic daily dosing of TS inhibitors can however give some antitumor activity in mice. Athymic mice bearing IGROV-1 xenografts were dosed once daily for 14 days, and growth delay was evaluated using the median time for the tumor volume to increase 4-fold ( 6 and 11.5 days in controls and treated animals respectively; p=0.01). No weight loss was observed. These data suggest that, in spite of the challenges associated with evaluation of TS inhibitors in mice, BGC 945 induces significant antitumor activity at a dose that induces no obvious toxicity, and demonstrates that both the efficacy and tolerability of BGC 945 is mediated through its selectivity for TS and the α-FR. This work is funded by Cancer Research UK and BTG International.