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

2.50
Hdl Handle:
http://hdl.handle.net/10541/90771
Title:
Tetrazepinones are equally cytotoxic to Mer+ and Mer- human tumor cell lines.
Authors:
Jean-Claude, Bertrand J; Mustafa, Amir; Watson, Amanda J; Damian, Zoe; Vasilescu, Daniela; Chan, Tak Hang; Leyland-Jones, Brian
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.
Affiliation:
Department of Oncology, McGill University, Montreal, Quebec, Canada.
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
Issue Date:
Feb-1999
URI:
http://hdl.handle.net/10541/90771
PubMed ID:
9918549
Type:
Article
Language:
en
ISSN:
0022-3565
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorJean-Claude, Bertrand Jen
dc.contributor.authorMustafa, Amiren
dc.contributor.authorWatson, Amanda Jen
dc.contributor.authorDamian, Zoeen
dc.contributor.authorVasilescu, Danielaen
dc.contributor.authorChan, Tak Hangen
dc.contributor.authorLeyland-Jones, Brianen
dc.date.accessioned2010-01-28T13:59:42Z-
dc.date.available2010-01-28T13:59:42Z-
dc.date.issued1999-02-
dc.identifier.citationTetrazepinones are equally cytotoxic to Mer+ and Mer- human tumor cell lines. 1999, 288 (2):484-9 J. Pharmacol. Exp. Ther.en
dc.identifier.issn0022-3565-
dc.identifier.pmid9918549-
dc.identifier.urihttp://hdl.handle.net/10541/90771-
dc.description.abstractHuman 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.en
dc.language.isoenen
dc.subjectBrain Canceren
dc.subjectColonic Canceren
dc.subjectCultured Tumour Cellsen
dc.subject.meshAntineoplastic Agents, Alkylating-
dc.subject.meshBenzazepines-
dc.subject.meshBrain Neoplasms-
dc.subject.meshCell Cycle-
dc.subject.meshColonic Neoplasms-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshFlow Cytometry-
dc.subject.meshGlioma-
dc.subject.meshHumans-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshPhenotype-
dc.subject.meshPyridines-
dc.subject.meshTumor Cells, Cultured-
dc.titleTetrazepinones are equally cytotoxic to Mer+ and Mer- human tumor cell lines.en
dc.typeArticleen
dc.contributor.departmentDepartment of Oncology, McGill University, Montreal, Quebec, Canada.en
dc.identifier.journalJournal of Pharmacology and Experimental Therapeuticsen

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