RT Journal Article
SR Electronic
T1 Tetrazepinones Are Equally Cytotoxic to Mer+ and Mer− Human Tumor Cell Lines
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 484
OP 489
VO 288
IS 2
A1 Bertrand J. Jean-Claude
A1 Amir Mustafa
A1 Amanda J. Watson
A1 Zoe Damian
A1 Daniela Vasilescu
A1 Tak Hang Chan
A1 Brian Leyland-Jones
YR 1999
UL http://jpet.aspetjournals.org/content/288/2/484.abstract
AB Human brain and colon tumor cell lines SF-188 (Mer+) and WiDR (Mer+), which express the DNA repair proteinO6-methylguanine-DNA methyl transferase (MGMT), were 3- to 30-fold less sensitive to temozolomide, mitozolomide, andN,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 μM) 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. The American Society for Pharmacology and Experimental Therapeutics