BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors.

Abstract

BGC 945 is a cyclopenta[g]quinazoline-based, thymidylate synthase inhibitor specifically transported into alpha-folate receptor (alpha-FR)-overexpressing tumors. Affinity of BGC 945 for the alpha-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 alpha-FR-negative mouse L1210 or human A431 cells is approximately 7 micromol/L. In contrast, BGC 945 is highly potent in a range of alpha-FR-overexpressing human tumor cell lines (IC(50) approximately 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 approximately 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-[(125)I]-iodo-2'-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 alpha-FR-overexpressing tumors and should cause minimal toxicity to humans at therapeutic doses.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 24 Pg. 11721-8 (Dec 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16357184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BGC945
• Carrier Proteins
• Enzyme Inhibitors
• Folate Receptors, GPI-Anchored
• Iodine Radioisotopes
• Membrane Transport Proteins
• Quinazolines
• Receptors, Cell Surface
• Reduced Folate Carrier Protein
• SLC19A1 protein, human
• Slc19a1 protein, mouse
• Folic Acid
• Thymidylate Synthase
• Idoxuridine

Topics

• Animals
• Apoptosis (drug effects)
• Biological Transport
• Carrier Proteins (metabolism)
• Cell Proliferation (drug effects)
• Choriocarcinoma (drug therapy, enzymology)
• Enzyme Inhibitors (pharmacokinetics, pharmacology)
• Female
• Folate Receptors, GPI-Anchored
• Folic Acid (metabolism)
• Humans
• Idoxuridine (metabolism)
• Iodine Radioisotopes
• Leukemia L1210 (drug therapy, enzymology)
• Lung Neoplasms (drug therapy, enzymology)
• Membrane Transport Proteins
• Mice
• Mice, Nude
• Ovarian Neoplasms (drug therapy, enzymology)
• Quinazolines (pharmacokinetics, pharmacology)
• Receptors, Cell Surface (metabolism)
• Reduced Folate Carrier Protein
• Thymidylate Synthase (antagonists & inhibitors)
• Tissue Distribution
• Transplantation, Heterologous
• Tumor Cells, Cultured