Comparative pharmacokinetics of DNA lesion formation and removal following treatment of L1210 cells with nitrogen mustards.
The kinetics of formation and removal of DNA interstrand crosslinks (ISC), DNA-protein crosslinks (DPC), and single strand breaks (SSB) by several nitrogen mustards were compared in order to determine the degree to which lesion selectivity may vary. The kinetic measurements using DNA alkaline elution methodology were obtained in mouse L1210 cells treated with mechlorethamine (HN2), phenylalanine mustard (L-PAM), uracil mustard (UM), 6-methyl-UM, and quinacrine mustard (QM). The ISC or DPC challenge delivered to cells was gauged on the basis of the kinetics as either total ISC or DPC produced, or as the area under the lesions versus time curve (AUC). By either measure (excepting QM), ISC correlated well with loss of colony survival, whereas DPC did not. The ISC/DPC ratio may therefore be a useful index of lesion selectivity. This ratio was significantly greater for 6-methyl-UM than for HN2. The ratio was also greater for L-PAM than for HN2 but only when gauged by AUC; this was attributable to an unusually slow rate for ISC removal in the case of L-PAM. The preferential reaction of UM at some 5'-GC-3' sites in purified DNA had suggested that UM might produce ISC with increased efficacy. UM, however, was somewhat less efficacious in ISC production than was 6-methyl-UM, which lacked selectivity for alkylation at 5'-GC-3'. QM was the only compound that produced detectable SSB, and the SSB were so numerous that ISC could not be quantitated.(ABSTRACT TRUNCATED AT 250 WORDS)
O'Connor
P M
PM
Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Kohn
K W
KW
D000818:Animals; D003114:Colony-Forming Units Assay; D003198:Computer Simulation; D003434:Crossing Over, Genetic; D004249:DNA Damage; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy*; D008466:Mechlorethamine / Q000494:pharmacology; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D011797:Quinacrine Mustard / Q000494:pharmacology; D014499:Uracil Mustard / Q000031:analogs & derivatives / Q000494:pharmacology
D009588:Nitrogen Mustard Compounds; C006994:chloroethylaminouracil; D011797:Quinacrine Mustard; D008466:Mechlorethamine; D008558:Melphalan; D014499:Uracil Mustard