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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