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

Publication ,  Journal Article
Bacolod, MD; Fehdrau, R; Johnson, SP; Bullock, NS; Bigner, DD; Colvin, M; Friedman, HS
Published in: Cancer Chemother Pharmacol
March 2009

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).

Duke Scholars

Published In

Cancer Chemother Pharmacol

DOI

EISSN

1432-0843

Publication Date

March 2009

Volume

63

Issue

4

Start / End Page

753 / 758

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Oncology & Carcinogenesis
  • Metallothionein
  • Medulloblastoma
  • Humans
  • Drug Resistance, Neoplasm
  • Cerebellar Neoplasms
  • Carmustine
  • 3214 Pharmacology and pharmaceutical sciences
  • 3211 Oncology and carcinogenesis
 

Citation

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ICMJE
MLA
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Bacolod, M. D., Fehdrau, R., Johnson, S. P., Bullock, N. S., Bigner, D. D., Colvin, M., & Friedman, H. S. (2009). BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line. Cancer Chemother Pharmacol, 63(4), 753–758. https://doi.org/10.1007/s00280-008-0792-9
Bacolod, Manny D., Randy Fehdrau, Stewart P. Johnson, Nancy S. Bullock, Darell D. Bigner, Michael Colvin, and Henry S. Friedman. “BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line.Cancer Chemother Pharmacol 63, no. 4 (March 2009): 753–58. https://doi.org/10.1007/s00280-008-0792-9.
Bacolod MD, Fehdrau R, Johnson SP, Bullock NS, Bigner DD, Colvin M, et al. BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line. Cancer Chemother Pharmacol. 2009 Mar;63(4):753–8.
Bacolod, Manny D., et al. “BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line.Cancer Chemother Pharmacol, vol. 63, no. 4, Mar. 2009, pp. 753–58. Pubmed, doi:10.1007/s00280-008-0792-9.
Bacolod MD, Fehdrau R, Johnson SP, Bullock NS, Bigner DD, Colvin M, Friedman HS. BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line. Cancer Chemother Pharmacol. 2009 Mar;63(4):753–758.
Journal cover image

Published In

Cancer Chemother Pharmacol

DOI

EISSN

1432-0843

Publication Date

March 2009

Volume

63

Issue

4

Start / End Page

753 / 758

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Oncology & Carcinogenesis
  • Metallothionein
  • Medulloblastoma
  • Humans
  • Drug Resistance, Neoplasm
  • Cerebellar Neoplasms
  • Carmustine
  • 3214 Pharmacology and pharmaceutical sciences
  • 3211 Oncology and carcinogenesis