PMID- 8068041
OWN - NLM
STAT- MEDLINE
DCOM- 19940920
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 48
IP  - 3
DP  - 1994 Aug 3
TI  - Combined depletion of O6-alkylguanine-DNA alkyltransferase and glutathione to 
      modulate nitrosourea resistance in breast cancer.
PG  - 543-8
AB  - MCF-7 human breast cancer cells possess high levels of O6-alkylguanine-DNA 
      alkyltransferase and moderate levels of glutathione, and are more resistant to 
      chloroethylnitrosoureas (CNUs) than cells with low levels of either molecule. The 
      role of each as a component of CNU resistance was assessed using O6-benzylguanine 
      (O6-bG) or O6-methylguanine (O6-mG) to deplete the alkyltransferase and 
      L-buthionine sulfoxamine (L-BSO) to deplete glutathione. O6-bG and O6-mG 
      potentiated 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) cytotoxicity, resulting 
      in a dose modification factor of 5.4 and 2.3, respectively, which reflected the 
      more potent inhibitory effect of O6-bG. L-BSO alone had little effect on the 
      survival of MCF-7 cells following BCNU exposure, but when combined with O6-mG, 
      BCNU cytotoxicity was additive, yielding a dose modification factor of 3.2. O6-bG 
      or O6-mG and L-BSO acted independently, as neither class of inhibitor affected 
      the other's mechanism of CNU resistance. Furthermore, MCF-7 cells overexpressing 
      GST mu were not more resistant to BCNU than the parent cell line in either the 
      presence or absence of O6-bG or L-BSO. These results indicate that on a relative 
      basis in MCF-7 cells, the alkyltransferase is the cell's first line of defense 
      against CNUs. This suggests that therapeutic trials based on O6-bG-induced 
      biochemical modulation of CNU resistance may increase the efficacy of these 
      chemotherapeutic agents against human malignant cells and that L-BSO may have 
      little additive effect when used with these agents.
FAU - Gerson, S L
AU  - Gerson SL
AD  - Department of Medicine, University Hospitals of Cleveland, OH.
FAU - Berger, S J
AU  - Berger SJ
FAU - Varnes, M E
AU  - Varnes ME
FAU - Donovan, C
AU  - Donovan C
LA  - eng
GR  - P01CA51183/CA/NCI NIH HHS/United States
GR  - P30CA43703/CA/NCI NIH HHS/United States
GR  - UO1CA57725/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  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 01KC87F8FE (O(6)-benzylguanine)
RN  - 2365-30-2 (1-(2-chloroethyl)-1-nitrosourea)
RN  - 5Z93L87A1R (Guanine)
RN  - 9B710FV2AE (O-(6)-methylguanine)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - EC 2.5.1.18 (Glutathione Transferase)
RN  - GAN16C9B8O (Glutathione)
RN  - P8M1T4190R (Ethylnitrosourea)
RN  - U68WG3173Y (Carmustine)
SB  - IM
MH  - Breast Neoplasms/*metabolism
MH  - Carmustine/pharmacology
MH  - Cell Line
MH  - Cell Survival
MH  - Drug Resistance
MH  - Ethylnitrosourea/*analogs & derivatives/pharmacology
MH  - Glutathione/*antagonists & inhibitors
MH  - Glutathione Transferase/analysis
MH  - Guanine/analogs & derivatives/pharmacology
MH  - Humans
MH  - Methyltransferases/*antagonists & inhibitors
MH  - O(6)-Methylguanine-DNA Methyltransferase
EDAT- 1994/08/03 00:00
MHDA- 1994/08/03 00:01
CRDT- 1994/08/03 00:00
PHST- 1994/08/03 00:00 [pubmed]
PHST- 1994/08/03 00:01 [medline]
PHST- 1994/08/03 00:00 [entrez]
AID - 0006-2952(94)90284-4 [pii]
AID - 10.1016/0006-2952(94)90284-4 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 1994 Aug 3;48(3):543-8. doi: 10.1016/0006-2952(94)90284-4.