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

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posted on 2023-03-30, 16:49 authored by David D. Gibbs, Davinder S. Theti, Nadya Wood, Matthew Green, Florence Raynaud, Melanie Valenti, Martin D. Forster, Fraser Mitchell, Vassilios Bavetsias, Elisa Henderson, Ann L. Jackman
Supplementary Methods from BGC 945, a Novel Tumor-Selective Thymidylate Synthase Inhibitor Targeted to α-Folate Receptor–Overexpressing Tumors

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ARTICLE ABSTRACT

BGC 945 is a cyclopenta[g]quinazoline–based, thymidylate synthase inhibitor specifically transported into α-folate receptor (α-FR)–overexpressing tumors. Affinity of BGC 945 for the α-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 Ki for isolated thymidylate synthase is 1.2 nmol/L and the IC50 for inhibition of the growth of α-FR-negative mouse L1210 or human A431 cells is ∼7 μmol/L. In contrast, BGC 945 is highly potent in a range of α-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 α-FR-overexpressing tumors and should cause minimal toxicity to humans at therapeutic doses. (Cancer Res 2005; 65(24): 11721-8)

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