PMID- 9918549
OWN - NLM
STAT- MEDLINE
DCOM- 19990222
LR  - 20061115
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 288
IP  - 2
DP  - 1999 Feb
TI  - Tetrazepinones are equally cytotoxic to Mer+ and Mer- human tumor cell lines.
PG  - 484-9
AB  - 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.
FAU - Jean-Claude, B J
AU  - Jean-Claude BJ
AD  - Department of Oncology, McGill University, Montreal, Quebec, Canada.
FAU - Mustafa, A
AU  - Mustafa A
FAU - Watson, A J
AU  - Watson AJ
FAU - Damian, Z
AU  - Damian Z
FAU - Vasilescu, D
AU  - Vasilescu D
FAU - Chan, T H
AU  - Chan TH
FAU - Leyland-Jones, B
AU  - Leyland-Jones B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Benzazepines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Pyridines)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
SB  - IM
MH  - Antineoplastic Agents, Alkylating/*pharmacology
MH  - Benzazepines/*pharmacology
MH  - Brain Neoplasms/*drug therapy/enzymology
MH  - Cell Cycle/drug effects
MH  - Colonic Neoplasms/*drug therapy/enzymology
MH  - Enzyme Inhibitors/*pharmacology
MH  - Flow Cytometry
MH  - Glioma/*drug therapy/enzymology
MH  - Humans
MH  - O(6)-Methylguanine-DNA Methyltransferase/antagonists & inhibitors/*metabolism
MH  - Phenotype
MH  - Pyridines/*pharmacology
MH  - Tumor Cells, Cultured
EDAT- 1999/01/26 00:00
MHDA- 1999/01/26 00:01
CRDT- 1999/01/26 00:00
PHST- 1999/01/26 00:00 [pubmed]
PHST- 1999/01/26 00:01 [medline]
PHST- 1999/01/26 00:00 [entrez]
PST - ppublish
SO  - J Pharmacol Exp Ther. 1999 Feb;288(2):484-9.