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 journalArticle

29 Citations (Scopus)

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 (0-160μM) 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
Volume63
Issue number7
DOIs
StatePublished - Apr 1 2002

Fingerprint

Pharmacodynamics
Carmustine
Pharmacokinetics
Cell death
Cell Death
DNA
Cytotoxicity
Cell Cycle
In Vitro Techniques
Cells
G2 Phase
Alkylating Agents
Enzyme activity
Pharmaceutical Preparations
Cell Division
Half-Life
Permeability
Brain
Repair
Necrosis

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

In vitro pharmacokinetics and pharmacodynamics of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). / Ueda-Kawamitsu, Hiroko; Lawson, Terence A; Gwilt, Peter R.

In: Biochemical Pharmacology, Vol. 63, No. 7, 01.04.2002, p. 1209-1218.

Research output: Contribution to journalArticle

Ueda-Kawamitsu, Hiroko ; Lawson, Terence A ; Gwilt, Peter R. / In vitro pharmacokinetics and pharmacodynamics of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). In: Biochemical Pharmacology. 2002 ; Vol. 63, No. 7. pp. 1209-1218.
@article{363c5fee546d4efdaa6a1c5bbb141520,
title = "In vitro pharmacokinetics and pharmacodynamics of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)",
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 (0-160μM) 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.",
keywords = "BCNU, Cell cycle, Cell death, DNA interstrand cross-links, Pharmacodynamics, Pharmacokinetics",
author = "Hiroko Ueda-Kawamitsu and Lawson, {Terence A} and Gwilt, {Peter R.}",
year = "2002",
month = "4",
day = "1",
doi = "10.1016/S0006-2952(02)00878-X",
language = "English (US)",
volume = "63",
pages = "1209--1218",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "7",

}

TY - JOUR

T1 - In vitro pharmacokinetics and pharmacodynamics of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)

AU - Ueda-Kawamitsu, Hiroko

AU - Lawson, Terence A

AU - Gwilt, Peter R.

PY - 2002/4/1

Y1 - 2002/4/1

N2 - 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.

AB - 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.

KW - BCNU

KW - Cell cycle

KW - Cell death

KW - DNA interstrand cross-links

KW - Pharmacodynamics

KW - Pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=0036537035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036537035&partnerID=8YFLogxK

U2 - 10.1016/S0006-2952(02)00878-X

DO - 10.1016/S0006-2952(02)00878-X

M3 - Article

VL - 63

SP - 1209

EP - 1218

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 7

ER -