PMID- 9816224
OWN - NLM
STAT- MEDLINE
DCOM- 19990210
LR  - 20181201
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 2
IP  - 4
DP  - 1996 Apr
TI  - Role of O6-methylguanine-DNA methyltransferase in resistance of human brain tumor 
      cell lines to the clinically relevant methylating agents temozolomide and 
      streptozotocin.
PG  - 735-41
AB  - We have analyzed the sensitivity of 14 human medulloblastoma- and glioma-derived 
      cell lines to the clinically used methylating agents temozolomide and 
      streptozotocin. The cell lines responded similarly to these agents, displaying a 
      3-fold range in cytotoxicity, assessed as the 10% survival dose (LD10). The 
      contribution of O6-methylguanine-DNA methyltransferase (MGMT) to resistance, 
      measured as reduction in the LD10 by O6-benzylguanine (O6-BG), varied among the 
      lines by 1 order of magnitude for both agents. However, in all MGMT-expressing 
      lines, O6-BG eliminated a threshold dose that accounted for up to one-half of the 
      LD10. The effect of O6-BG on the rate of killing varied 13-fold for temozolomide 
      and 14-fold for streptozotocin. Some lines displayed two subpopulations with 
      different rates of killing, with one subpopulation that comprised 20-60% of cells 
      showing essentially no dependence of the rate of killing on MGMT. O6-BG increased 
      the range of the LD10 for both agents. The persistent, heightened variability in 
      cytotoxicity in the absence of MGMT, the lack of correlation between MGMT content 
      of the lines and cytoxicity (LD10), and the lack of correlation between MGMT 
      content and the contribution of MGMT to resistance (O6-BG-mediated reduction of 
      the LD10) reflect the operation of resistance mechanisms other than MGMT. We also 
      analyzed sensitivity to methyl methanesulfonate, observing little dependence of 
      resistance on MGMT and persistent variability in cytotoxicity in the presence of 
      O6-BG. We discuss the implications for clinical use of methylators and O6-BG.
FAU - Bobola, M S
AU  - Bobola MS
AD  - Departments of Neurosurgery and Pathology, University of Washington, Seattle, 
      Washington 98195, USA.
FAU - Tseng, S H
AU  - Tseng SH
FAU - Blank, A
AU  - Blank A
FAU - Berger, M S
AU  - Berger MS
FAU - Silber, J R
AU  - Silber JR
LA  - eng
GR  - OIG-R35-CA39903/CA/NCI NIH HHS/United States
GR  - T32CA09437/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 01KC87F8FE (O(6)-benzylguanine)
RN  - 12H3O2UGSF (Methylnitronitrosoguanidine)
RN  - 5W494URQ81 (Streptozocin)
RN  - 5Z93L87A1R (Guanine)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - AT5C31J09G (Methyl Methanesulfonate)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Antineoplastic Agents, Alkylating/*pharmacology
MH  - Brain Neoplasms/*drug therapy/pathology
MH  - Dacarbazine/*analogs & derivatives/pharmacology
MH  - Drug Resistance, Neoplasm
MH  - Guanine/analogs & derivatives/pharmacology
MH  - Humans
MH  - Methyl Methanesulfonate/pharmacology
MH  - Methylation
MH  - Methylnitronitrosoguanidine/pharmacology
MH  - O(6)-Methylguanine-DNA Methyltransferase/analysis/*physiology
MH  - Streptozocin/*pharmacology
MH  - Temozolomide
MH  - Tumor Cells, Cultured
EDAT- 1996/04/01 00:00
MHDA- 1998/11/17 00:01
CRDT- 1996/04/01 00:00
PHST- 1996/04/01 00:00 [pubmed]
PHST- 1998/11/17 00:01 [medline]
PHST- 1996/04/01 00:00 [entrez]
PST - ppublish
SO  - Clin Cancer Res. 1996 Apr;2(4):735-41.