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 [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.
Bailey
E
E
MRC Toxicology Unit, Carshalton, Surrey, U.K.
Farmer
P B
PB
Tang
Y S
YS
Vangikar
H
H
Gray
A
A
Slee
D
D
Ings
R M
RM
Campbell
D B
DB
McVie
J G
JG
Dubbelman
R
R
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
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