title: Hydroxyethylation of hemoglobin by 1-(2-chloroethyl)-1-nitrosoureas.
abstract: Following treatment of cancer patients with three 1-(2-chloroethyl)-1-nitrosoureas, hemoglobin was isolated and analyzed by GC-MS for N-(2-hydroxyethyl)-N-terminal valine. This alkylated amino acid was liberated as a (pentafluorophenyl)thiohydantoin from the hemoglobin by a modified Edman degradation procedure. Following intravenous infusion of fotemustine [diethyl[1-[3-(2-chloroethyl)-3-nitrosoureido]ethylphosphonate] (ca. 90 mg/m2) the levels of (hydroxyethyl)valine in two patients increased steadily, reaching a peak of ca. 300 pmol/g after 6 h. In a further five patients receiving fotemustine (100 mg/m2) alkylation levels 24 h after treatment ranged from 132 to 1524 pmol/g of globin. Treatment with TCNU [1-(2-chloroethyl)-3-[2-[(dimethylamino)sulfonyl]ethyl]-1- nitrosourea] or ACNU [1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-(2-chloroethyl)-3- nitrosourea] resulted in similar increases in (hydroxyethyl)valine in hemoglobin, although the amounts (as with fotemustine) showed considerable interindividual variation. It appears that the measurement of (hydroxyethyl)valine in hemoglobin may be a suitable monitor of exposure to hydroxyethylating agents during (chloroethyl)nitrosourea chemotherapy.
authors.affiliation: MRC Toxicology Unit, Carshalton, Surrey, U.K.
authors.forename: E
authors.initials: E
authors.lastname: Bailey
authors.forename: P B
authors.initials: PB
authors.lastname: Farmer
authors.forename: Y S
authors.initials: YS
authors.lastname: Tang
authors.forename: H
authors.initials: H
authors.lastname: Vangikar
authors.forename: A
authors.initials: A
authors.lastname: Gray
authors.forename: D
authors.initials: D
authors.lastname: Slee
authors.forename: R M
authors.initials: RM
authors.lastname: Ings
authors.forename: D B
authors.initials: DB
authors.lastname: Campbell
authors.forename: J G
authors.initials: JG
authors.lastname: McVie
authors.forename: R
authors.initials: R
authors.lastname: Dubbelman
mesh_terms: D000478:Alkylation; D000970:Antineoplastic Agents / Q000378:metabolism*; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D008297:Male; D015376:Nimustine / Q000378:metabolism*; D009607:Nitrosourea Compounds / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism*; D013654:Taurine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006454:Hemoglobins; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D015376:Nimustine; D013654:Taurine; C052991:1-(2-chloroethyl)-3-(2-(dimethylaminosulfonyl)ethyl)-1-nitrosourea; C054368:fotemustine