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Repair analysis of 4-hydroperoxycyclophosphamide-induced DNA interstrand crosslinking in the c-myc gene in 4-hydroperoxycyclophosphamide-sensitive and -resistant medulloblastoma cell lines.

Publication ,  Journal Article
Dong, Q; Bullock, N; Ali-Osman, F; Colvin, OM; Bigner, DD; Friedman, HS
Published in: Cancer Chemother Pharmacol
1996

Cyclophosphamide is one of the most active agents in the treatment of medulloblastoma. However, development of resistance to this alkylator frequently occurs and is the harbinger of tumor progression and death. In order to understand the biochemical basis of this resistance, we generated a panel of medulloblastoma cell lines in our laboratory that were resistant to 4-hydroperoxycyclophosphamide (4-HC). Previously, we have shown that elevated levels of aldehyde dehydrogenase and glutathione mediate cellular resistance to 4-HC. The present study was conducted to identify the third unknown mechanism mediating the resistance of cell line D283 Med (4-HCR) to 4-HC, testing the hypothesis that this resistance is mediated by an increased repair of DNA interstrand crosslinks (ICLs). The doses of 4-HC that produced a one- and two-log cell kill of D283 Med cells were 25 and 50 microM, respectively, compared with values of 125 and 165 microM in D283 Med (4-HCR), the resistant cell line. The formation and disappearance of 4-HC-induced DNA ICLs at the c-myc gene were subsequently studied by DNA denaturing/renaturing gel electrophoresis and Southern blot analysis. 4-HC-induced DNA ICLs in the c-myc gene exhibited a dose-dependent relationship. The percentage of the c-myc gene that was crosslinked was approximately 1-3% at a dose of 100 microM. More than 50% of the DNA crosslinking in D283 Med (4-HCR) cells was removed by 6 h after drug treatment, whereas, in D283 Med cells, more than 90% of the DNA crosslinking was still present at 6 h. These findings suggest that the increased repair of DNA ICLs in D283 Med (4-HCR) may contribute significantly to its resistance to 4-HC.

Duke Scholars

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1996

Volume

37

Issue

3

Start / End Page

242 / 246

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Oncology & Carcinogenesis
  • Medulloblastoma
  • Humans
  • Genes, myc
  • Electrophoresis
  • Drug Resistance, Neoplasm
  • DNA, Neoplasm
  • Cyclophosphamide
  • Cross-Linking Reagents
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Dong, Q., Bullock, N., Ali-Osman, F., Colvin, O. M., Bigner, D. D., & Friedman, H. S. (1996). Repair analysis of 4-hydroperoxycyclophosphamide-induced DNA interstrand crosslinking in the c-myc gene in 4-hydroperoxycyclophosphamide-sensitive and -resistant medulloblastoma cell lines. Cancer Chemother Pharmacol, 37(3), 242–246. https://doi.org/10.1007/BF00688323
Dong, Q., N. Bullock, F. Ali-Osman, O. M. Colvin, D. D. Bigner, and H. S. Friedman. “Repair analysis of 4-hydroperoxycyclophosphamide-induced DNA interstrand crosslinking in the c-myc gene in 4-hydroperoxycyclophosphamide-sensitive and -resistant medulloblastoma cell lines.Cancer Chemother Pharmacol 37, no. 3 (1996): 242–46. https://doi.org/10.1007/BF00688323.
Journal cover image

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1996

Volume

37

Issue

3

Start / End Page

242 / 246

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Oncology & Carcinogenesis
  • Medulloblastoma
  • Humans
  • Genes, myc
  • Electrophoresis
  • Drug Resistance, Neoplasm
  • DNA, Neoplasm
  • Cyclophosphamide
  • Cross-Linking Reagents