title: KW-2149 (7-N-[2-[gamma-L-glutamylamino]ethyldithioethyl]mitomycin C). A new mitomycin C analogue activated by serum.
abstract: KW-2149 (7-N-[2-[gamma-L-glutamylamino]ethyldithioethyl]mitomycin C) is a new mitomycin-C analogue in clinical trial. This study demonstrates that KW-2149, unlike mitomycin C, is activated to a cytotoxic species by extracellular metabolism in serum. The metabolising activity differs between batches of serum and species of origin. Human serum had high activity (which resulted in a 150-fold enhancement of cytotoxicity), whereas mouse serum had low activity. In the presence of serum, the rate of uptake of 3H-KW-2149 into cells increased by 8-fold and drug binding to DNA by 32-fold. The metabolising activity of serum can partially be replaced by glutathione. No anticancer drug has previously been described whose toxicity is mediated by metabolism in serum.
authors.affiliation: University College London, Institute of Urology and Nephrology, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Masters
authors.forename: R J
authors.initials: RJ
authors.lastname: Know
authors.forename: J A
authors.initials: JA
authors.lastname: Hartley
authors.forename: L R
authors.initials: LR
authors.lastname: Kelland
authors.forename: H R
authors.initials: HR
authors.lastname: Hendriks
authors.forename: T
authors.initials: T
authors.lastname: Connors
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001711:Biotransformation; D001769:Blood / Q000378:metabolism*; D018736:DNA Adducts / Q000032:analysis; D006801:Humans; D051379:Mice; D016685:Mitomycin / Q000378:metabolism / Q000494:pharmacology; D008937:Mitomycins; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D008937:Mitomycins; C057625:KW 2149; D016685:Mitomycin