title: Functional and chemical markers of PCNU activity.
abstract: A study was conducted to elucidate functional or chemical parameters that may be useful for in vivo toxicologic and pharmacokinetic analysis of PCNU. The growth-inhibitory and DNA-related parameters of this agent and its serum breakdown products in murine leukemia L1210 cells were carried out in direct comparison with BCNU. In human and dog sera, the T1/2 of intact PCNU (5-12 min) was similar to BCNU (5-16 min). However, much larger T1/2 values for PCNU (140 min) and BCNU (110 min) were determined for drug incubated in dog brain homogenates. Uptake of 14C-labeled PCNU in L1210 cells was rapid, and tenfold higher than in CCRF-CEM, a human leukemia cell line naturally resistant to BCNU and PCNU. BCNU was shown to induce DNA strand damage in L1210 and to inhibit radioactive thymidine incorporation into DNA and cross-link proteins with DNA in L1210. PCNU, by comparison, only weakly inhibited thymidine incorporation and did not induce DNA strand breakage or produce DNA-protein cross-links in L1210 at reasonable concentrations. The compounds are further differentiated in fetal calf serum by the breakdown products derived from initial concentrations of intact drug that are equipotent; those of BCNU inhibit L1210 growth whereas those of PCNU do not. PCNU, which is rapidly broken down into inactive metabolites, may have a selective therapeutic advantage if infused directly to the target site.
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D051379:Mice; D009607:Nitrosourea Compounds / Q000378:metabolism / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D004247:DNA; C018627:1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidinyl)-1-nitrosourea; D002330:Carmustine; D013936:Thymidine; D010634:Phenobarbital