In vitro pharmacokinetics and pharmacodynamics of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)

Hiroko Ueda-Kawamitsu, Terence A. Lawson, Peter R. Gwilt

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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 (0-160μM) and analyzed for intracellular BCNU concentrations, DNA interstrand cross-links, cell cycle phase, and cytotoxicity. The half-life of BCNU in cells was ≈40min. The maximum reduction of mitochondrial enzyme activity (maximum cell death) achieved within 24hr 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 G2/M phase of the cell cycle, which continued even after apparent completion of cross-link repair. Loss of membrane permeability was minimal (≈2%) during the first 24hr. 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.

Original languageEnglish (US)
Pages (from-to)1209-1218
Number of pages10
JournalBiochemical Pharmacology
Issue number7
StatePublished - Apr 1 2002


  • BCNU
  • Cell cycle
  • Cell death
  • DNA interstrand cross-links
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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