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Inactivation of p53 Sensitizes Astrocytic Glioma Cells to BCNU and Temozolomide, but not Cisplatin

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Summary

p53 inactivation sensitizes U87MG astrocytic glioma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ), drugs used clinically to treat high-grade astrocytomas. In this report, we examined the effect of p53 inactivation on the chemosensitivity of two additional human astrocytic glioma cell lines, D54 and A172, in order to assess whether sensitization is a general property of astrocytic tumor cells. Compared to control cells with intact p53 function, derived lines in which p53 was inactivated displayed significantly reduced clonogenic survival after exposure to BCNU and TMZ. Sensitization to both BCNU and TMZ was associated with failure of p21WAF1 induction, lack of a sustained G2 cell cycle arrest and significant tumor cell death. These findings suggest that enhanced sensitivity to BCNU and TMZ is a general property of human astrocytic glioma cells in which p53 was disrupted. In contrast, p53 inactivation rendered D54 and U87MG cells significantly more resistant to cis-dichlorodiamminoplatinum (CDDP), another chemotherapeutic to which high-grade astrocytomas sometimes respond. These results indicate that p53 status influences the chemosensitivity of astrocytic glioma cells in a drug-type specific manner, a finding that may have implications for the selection of drug treatments for patients with astrocytic gliomas.

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Abbreviations

BCNU:

1,3-bis (2-chloroethyl)-1-nitrosourea

CDDP:

cis-dichlorodiammine platinum(II)

TMZ:

temozolomide

LD:

lethal dose

FBS:

fetal bovine serum

ECL:

enhanced chemiluminescence

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Authors and Affiliations

  1. Departments of Oncology, University of Western, Ontario, Canada

    G. Wei Xu, Joe S. Mymryk & J. Gregory Cairncross

  2. Neuroscience Program, University of Western Ontario, Ontario, Canada

    G. Wei Xu, Joe S. Mymryk & J. Gregory Cairncross

  3. Departments of Microbiology & Immunology, University of Western Ontario, Ontario, Canada

    Joe S. Mymryk

  4. The Cancer Research Laboratories, London Regional Cancer Centre, London, Ontario, Canada

    G. Wei Xu & Joe S. Mymryk

  5. Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada

    J. Gregory Cairncross

  6. Cairncoss Foothills Medical Centre, 1403 29th Street N.W., Calgary, T2N 2T9, Alberta, Canada

    J. Gregory Cairncross

Authors
  1. G. Wei Xu
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  2. Joe S. Mymryk
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  3. J. Gregory Cairncross
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Correspondence to J. Gregory Cairncross.

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Xu, G.W., Mymryk, J.S. & Cairncross, J.G. Inactivation of p53 Sensitizes Astrocytic Glioma Cells to BCNU and Temozolomide, but not Cisplatin. J Neurooncol 74, 141–149 (2005). https://doi.org/10.1007/s11060-004-6601-3

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  • DOI: https://doi.org/10.1007/s11060-004-6601-3

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