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BGC 945, a Novel Tumor-Selective Thymidylate Synthase Inhibitor Targeted to -Folate Receptor–Overexpressing Tumors

¹ Section of Medicine and ² Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, United Kingdom

Requests for reprints: Ann L. Jackman, The Institute of Cancer Research, The Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44-208-722-4284; Fax: 44-208-642-7979; E-mail: ann.jackman{at}icr.ac.uk.

BGC 945 is a cyclopenta[g]quinazoline–based, thymidylate synthase inhibitor specifically transported into -folate receptor (-FR)–overexpressing tumors. Affinity of BGC 945 for the -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 IC₅₀ for inhibition of the growth of -FR-negative mouse L1210 or human A431 cells is 7 µmol/L. In contrast, BGC 945 is highly potent in a range of -FR-overexpressing human tumor cell lines (IC₅₀ 1-300 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 1 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-[¹²⁵I]-iodo-2'-deoxyuridine ([¹²⁵I]dUrd) into DNA. Forty-eight hours after injection of 100 mg/kg 6RS-BGC 945 ([¹²⁵I]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 [¹²⁵I]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 -FR-overexpressing tumors and should cause minimal toxicity to humans at therapeutic doses. (Cancer Res 2005; 65(24): 11721-8)

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