ABSTRACT
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)
Subject(s)
Crossing Over, Genetic , DNA Damage , Leukemia L1210/drug therapy , Nitrogen Mustard Compounds/pharmacology , Animals , Colony-Forming Units Assay , Computer Simulation , In Vitro Techniques , Mechlorethamine/pharmacology , Melphalan/pharmacology , Mice , Quinacrine Mustard/pharmacology , Uracil Mustard/analogs & derivatives , Uracil Mustard/pharmacologyABSTRACT
In an early phase II study, fluorodopan (5-(2'-fluoroethyl-2'-chloroethyl)-amino-6-methyl uracil) was given to 17 patients with advanced colorectal cancer previously treated with multiple agents. Side effects included mild nausea and vomiting in 14 patients, platelet counts of less than 50,000/microliter in four patients, and wbc counts of less than 2000/microliter in two patients. Partial remission lasting 9 weeks was achieved in one patient, and stable disease with a mean duration of 7.1 weeks was achieved in ten patients. Given in this setting fluorodopan does not appear to have a significant effect in terms of regression of tumor or prolongation of survival.
