BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line.

Published

Journal Article

PURPOSE: Resistance of neoplastic cells to the alkylating drug BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] has been correlated with expression of O (6)-methylguanine-DNA methyltransferase, which repairs the O (6)-chloroethylguanine produced by the drug. Other possible mechanisms of resistance include raised levels of glutathione or increased repair of the DNA interstrand cross-links formed by BCNU. Transcriptional profiling revealed the upregulation of several metallothionein (MT) genes in a BCNU-resistant medulloblastoma cell line [D341 MED (OBR)] relative to its parental line. Previous studies have shown that MTs, through their reactive thiol groups can quench nitrogen mustard-derived alkylating drugs. In this report, we evaluate whether MTs can also quench BCNU. METHODS: To demonstrate the binding of BCNU to MT, we used an assay that measured the release of the MT-bound divalent cations (Zn(2+), Cd(2+)) upon their displacement by the drug. We also measured the decomposition rates of BCNU at those reaction conditions. RESULTS: The rate of release of the cations was higher in pH 7.4 than at pH 7.0, which is likely a result of more rapid decomposition of BCNU (thus faster release of MT-binding intermediate) at pH 7.4 than at pH 7.0. CONCLUSION: We demonstrate that resistance to BCNU may be a result of elevated levels of MTs which act by sequestering the drug's decomposition product(s).

Full Text

Duke Authors

Cited Authors

  • Bacolod, MD; Fehdrau, R; Johnson, SP; Bullock, NS; Bigner, DD; Colvin, M; Friedman, HS

Published Date

  • March 2009

Published In

Volume / Issue

  • 63 / 4

Start / End Page

  • 753 - 758

PubMed ID

  • 18633619

Pubmed Central ID

  • 18633619

Electronic International Standard Serial Number (EISSN)

  • 1432-0843

Digital Object Identifier (DOI)

  • 10.1007/s00280-008-0792-9

Language

  • eng

Conference Location

  • Germany