Hydroxyethylation of hemoglobin by 1-(2-chloroethyl)-1-nitrosoureas

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 diethyl1-3-(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.