PMID- 16698182
OWN - NLM
STAT- MEDLINE
DCOM- 20060811
LR  - 20161124
IS  - 0305-7372 (Print)
IS  - 0305-7372 (Linking)
VI  - 32
IP  - 4
DP  - 2006 Jun
TI  - Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance 
      chemotherapy.
PG  - 261-76
AB  - DNA adducts at the O6-position of guanine are a result of the carcinogenic, 
      mutagenic and cytotoxic actions of methylating and chloroethylating agents. The 
      presence of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) 
      renders cells resistant to the biological effects induced by agents that attack 
      at this position. O6-Benzylguanine (O6-BG) is a low molecular weight substrate of 
      AGT and therefore, results in sensitizing cells and tumors to alkylating 
      agent-induced cytotoxicity and antitumor activity. Presently, chemotherapy 
      regimens of O6-BG in combination with BCNU, temozolomide and Gliadel are in 
      clinical development. Other ongoing clinical trials include expression of mutant 
      AGT proteins that confer resistance to O6-BG in bone marrow stem cells, in an 
      effort to reduce the potential enhanced toxicity and mutagenicity of alkylating 
      agents in the bone marrow. O6-BG has also been found to enhance the cytotoxicity 
      of agents that do not form adducts at the O6-position of DNA, including 
      platinating agents. O6-BG's mechanism of action with these agents is not fully 
      understood; however, it is independent of AGT activity or AGT inactivation. A 
      better understanding of the effects of this agent will contribute to its clinical 
      usefulness and the design of better analogs to further improve cancer 
      chemotherapy.
FAU - Rabik, Cara A
AU  - Rabik CA
AD  - Department of Medicine, Committee on Cancer Biology, Committee on Clinical 
      Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL 60637, USA.
FAU - Njoku, Maria Chidiamara
AU  - Njoku MC
FAU - Dolan, M Eileen
AU  - Dolan ME
LA  - eng
GR  - 5 T32 GM07281/GM/NIGMS NIH HHS/United States
GR  - CA81485/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
DEP - 20060515
PL  - Netherlands
TA  - Cancer Treat Rev
JT  - Cancer treatment reviews
JID - 7502030
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Platinum Compounds)
RN  - 01KC87F8FE (O(6)-benzylguanine)
RN  - 5Z93L87A1R (Guanine)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - EC 6.5.1.- (DNA Repair Enzymes)
SB  - IM
MH  - Antineoplastic Agents/therapeutic use
MH  - Antineoplastic Agents, Alkylating/administration & dosage/*therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - DNA Repair Enzymes/*antagonists & inhibitors
MH  - Drug Resistance
MH  - Enzyme Inhibitors/administration & dosage/therapeutic use
MH  - Guanine/administration & dosage/analogs & derivatives/therapeutic use
MH  - Hematopoietic Stem Cells/drug effects
MH  - Humans
MH  - O(6)-Methylguanine-DNA Methyltransferase/*antagonists & inhibitors
MH  - Platinum Compounds/therapeutic use
RF  - 164
EDAT- 2006/05/16 09:00
MHDA- 2006/08/12 09:00
CRDT- 2006/05/16 09:00
PHST- 2006/01/10 00:00 [received]
PHST- 2006/03/14 00:00 [revised]
PHST- 2006/03/15 00:00 [accepted]
PHST- 2006/05/16 09:00 [pubmed]
PHST- 2006/08/12 09:00 [medline]
PHST- 2006/05/16 09:00 [entrez]
AID - S0305-7372(06)00056-9 [pii]
AID - 10.1016/j.ctrv.2006.03.004 [doi]
PST - ppublish
SO  - Cancer Treat Rev. 2006 Jun;32(4):261-76. doi: 10.1016/j.ctrv.2006.03.004. Epub 
      2006 May 15.