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Abstract
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.