In vitro pharmacokinetics and pharmacodynamics of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU).
The relationship between treatment efficacy and the pharmacokinetics (PK) and pharmacodynamics (PD) of anticancer drugs is poorly defined. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) is an alkylating agent used in the treatment of brain and other forms of cancer. It is postulated that BCNU kills cells by forming DNA interstrand cross-links. The present study was undertaken to characterize the PK and PD of BCNU in mouse L1210 cells. L1210 cells were exposed to BCNU (0-160 microM) and analyzed for intracellular BCNU concentrations, DNA interstrand cross-links, cell cycle phase, and cytotoxicity. The half-life of BCNU in cells was approximately 40 min. The maximum reduction of mitochondrial enzyme activity (maximum cell death) achieved within 24 hr after exposure to BCNU was concentration-dependent and could be described by a Hill equation. At lower concentrations, the area under the DNA interstrand cross-link-time curve linearly correlated with the maximum cell death and the area under the BCNU concentration-time curve. BCNU induced cell accumulation in the G(2)/M phase of the cell cycle, which continued even after apparent completion of cross-link repair. Loss of membrane permeability was minimal (approximately 2%) during the first 24 hr. Thereafter, cells died exponentially over the next 9 days, primarily by necrosis. In conclusion, while cytotoxicity was concentration-dependent, an indirect relationship was found among the time-course of BCNU concentrations, DNA interstrand cross-links, and cell death. Because of the disparity between the time-scale of PK and PD, focusing only on the early events may provide limited information about the process of anticancer drug-induced cell death.
Ueda-Kawamitsu
Hiroko
H
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 600 South 42nd Street, P.O. Box 986025, Omaha, NE 68198-6025, USA.
Lawson
Terence A
TA
Gwilt
Peter R
PR
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000494:pharmacology*; D002330:Carmustine / Q000493:pharmacokinetics / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007939:Leukemia L1210 / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D002330:Carmustine