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

Abstract

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).

• Authors: Manny D Bacolod, Randy Fehdrau, Stewart P Johnson, Nancy S Bullock, Darell D Bigner, Michael Colvin, Henry S Friedman
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 63 Issue 4 Pg. 753-8 (Mar 2009) ISSN: 1432-0843 [Electronic] Germany
• PMID: 18633619 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Metallothionein
• Carmustine

Topics

• Carmustine (metabolism)
• Cerebellar Neoplasms (metabolism)
• Drug Resistance, Neoplasm
• Humans
• Medulloblastoma (metabolism)
• Metallothionein (metabolism)
• Tumor Cells, Cultured