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Brain tumor cell lines resistant to O-6-benzylguanine/1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy have O-6 -alkylguanine-DNA alkyltransferase mutations

  1. Author:
    Bacolod, M. D.
    Johnson, S. P.
    Pegg, A. E.
    Dolan, M. E.
    Moschel, R. C.
    Bullock, N. S.
    Fang, Q. M.
    Colvin, O. M.
    Modrich, P.
    Bigner, D. D.
    Friedman, H. S.

  2. Author Address

    Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA. Penn State Univ, Coll Med, Milton S Hershey Med Ctr, Dept Cellular & Mol Physiol, Hershey, PA USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD USA Friedman, HS, Duke Univ, Med Ctr, Dept Surg, Box 3624, Durham, NC 27710 USA
    1. Year: 2004
    2. Date: SEP
  2. Journal: Molecular Cancer Therapeutics
    1. 3
    2. 9
    3. Pages: 1127-1135
  4. Type of Article: Article
  1. Abstract:

    The chemotherapeutic activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) may be improved by the addition of O-6-benzylguanine (O-6 -BG). The reaction of O-6-BG with O-6-alkylguanine-DNA alkyltransferase (AGT) prevents the repair of O-6-chloroethyl lesions caused by BCNU. In clinics, the combination of O-6-BG and BCNU is now being tested for the treatment of brain tumors. However, the effectiveness of this drug regimen may be limited by drug resistance acquired during treatment. To understand the possible mechanisms of resistance of brain tumor cells to the O-6-BG/BCNU combination, we generated medulloblastoma cell lines (D283 MED, D341 MED, and Daoy) resistant to the combination of O-6-BG and BCNU [O-6-BG/BCNU resistant (OBR)]. DNA sequencing showed that all of the parent cell lines express wild-type AGTs, whereas every OBR cell line exhibited mutations that potentially affected the binding of O-6-BG to the protein as evidenced previously by in vitro mutagenesis and structural studies of AGT. The D283 MED (OBR), Daoy (OBR), and D341 MED (OBR) cell lines expressed G156C, Y114F, and K165T AGT mutations, respectively. We reported previously that rhabdomyosarcoma TE-671 (OBR) also expresses a G156C mutation. These data suggest that the clonal selection of AGT mutants during treatment with O-6-BG plus an alkylator may produce resistance to this intervention in clinical settings

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External Sources

  1. View record in Web of Science®
  2. WOS: 000223907300010

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