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    Tetrazepinones are equally cytotoxic to Mer+ and Mer- human tumor cell lines.

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    Authors
    Jean-Claude, Bertrand J
    Mustafa, Amir
    Watson, Amanda J
    Damian, Zoe
    Vasilescu, Daniela
    Chan, Tak Hang
    Leyland-Jones, Brian
    Affiliation
    Department of Oncology, McGill University, Montreal, Quebec, Canada.
    Issue Date
    1999-02
    
    Metadata
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    Abstract
    Human brain and colon tumor cell lines SF-188 (Mer+) and WiDR (Mer+), which express the DNA repair protein O6-methylguanine-DNA methyl transferase (MGMT), were 3- to 30-fold less sensitive to temozolomide, mitozolomide, and N, N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) than the MGMT-deficient tumor cells SF-126 (Mer-) and BE (Mer-). This differential sensitivity was not observed when these cells were exposed to the novel tetrazepinones PYRZ, NIME, QUINCL, and PYRCL, which contain, like temozolomide and mitozolomide, a ureido-triazene moiety. Flow cytometric studies revealed that temozolomide induced G2-M arrest in the Mer- cells, but exerted a minor effect on the cycle of the Mer+ cells. Similarly, mitozolomide (25-100 microM) induced a stronger S-phase arrest in the SF-126 cells than in the SF-188 cells. In the same dose range (25-100) BCNU induced a significant cell cycle accumulation in G22-M in the SF-126 cells but little in the SF-188 cell line. In contrast, the cell cycle effects of the tetrazepinones were independent of the cell phenotypes. When O6-benzylguanine (O6-BG) was used to deplete MGMT activity in the SF brain tumor cell lines, significant potentiation of temozolomide (67-fold), mitozolomide (7-fold), and BCNU (3-fold) was observed in the SF-188 cell line. By contrast, O6-BG did not potentiate PYRZ, PYRCL, QUINCL, and NIME. Moreover, an MGMT inhibitory assay showed that all the tetrazepinones were capable of inactivating MGMT in the SF-188 cell line, the strongest inhibitor being PYRCL. The results suggest that, unlike temozolomide, mitozolomide, and BCNU, the cytotoxicity of the tetrazepinones does not correlate with the alkylation of the O6 position of guanine and that the mechanism of MGMT inactivation by tetrazepinones may differ from that of hitherto known inhibitors.
    Citation
    Tetrazepinones are equally cytotoxic to Mer+ and Mer- human tumor cell lines. 1999, 288 (2):484-9 J. Pharmacol. Exp. Ther.
    Journal
    Journal of Pharmacology and Experimental Therapeutics
    URI
    http://hdl.handle.net/10541/90771
    PubMed ID
    9918549
    Type
    Article
    Language
    en
    ISSN
    0022-3565
    Collections
    All Paterson Institute for Cancer Research

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