title: 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.affiliation: Section of Medicine and Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton.
authors.forename: David D
authors.initials: DD
authors.lastname: Gibbs
authors.forename: Davinder S
authors.initials: DS
authors.lastname: Theti
authors.forename: Nadya
authors.initials: N
authors.lastname: Wood
authors.forename: Matthew
authors.initials: M
authors.lastname: Green
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Martin D
authors.initials: MD
authors.lastname: Forster
authors.forename: Fraser
authors.initials: F
authors.lastname: Mitchell
authors.forename: Vassilios
authors.initials: V
authors.lastname: Bavetsias
authors.forename: Elisa
authors.initials: E
authors.lastname: Henderson
authors.forename: Ann L
authors.initials: AL
authors.lastname: Jackman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002822:Choriocarcinoma / Q000188:drug therapy / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism; D006801:Humans; D007065:Idoxuridine / Q000378:metabolism; D007457:Iodine Radioisotopes; D007939:Leukemia L1210 / Q000188:drug therapy / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D026901:Membrane Transport Proteins; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D058978:Reduced Folate Carrier Protein; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C504662:BGC945; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D058973:Folate Receptors, GPI-Anchored; D007457:Iodine Radioisotopes; D026901:Membrane Transport Proteins; D011799:Quinazolines; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C548700:Slc19a1 protein, mouse; D005492:Folic Acid; D013940:Thymidylate Synthase; D007065:Idoxuridine