PMID- 11103789
OWN - NLM
STAT- MEDLINE
DCOM- 20001222
LR  - 20161124
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 60
IP  - 22
DP  - 2000 Nov 15
TI  - O6-benzylguanine potentiates the antitumor effect of locally delivered carmustine 
      against an intracranial rat glioma.
PG  - 6307-10
AB  - Local delivery of carmustine (BCNU) via biodegradable polymers prolongs survival 
      against experimental brain tumors and in human clinical trials. O6-benzylguanine 
      (O6-BG), a potent inhibitor of the DNA repair protein, O6-alkylguanine-DNA 
      alkyltransferase (AGT), has been shown to reduce nitrosourea resistance and, 
      thus, enhance the efficacy of systemic BCNU therapy in a variety of tumor models. 
      In this report, we demonstrate that O6-BG can potentiate the activity of BCNU 
      delivered intracranially via polymers in rats challenged with a lethal brain 
      tumor. Fischer 344 rats received a lethal intracranial challenge of 100,000 F98 
      glioma cells (F98 cells have significant AGT activity, 328 fmol/mg protein). Five 
      days later, animals receiving an i.p. injection of O6-BG (50 mg/kg) 2 h prior to 
      BCNU polymer (3.8% BCNU by weight) implantation had significantly improved 
      survival (n = 7; median survival, 34 days) over animals receiving either O6-BG 
      alone (n = 7; median survival, 22 days; P = 0.0002) or BCNU polymer alone (n = 8; 
      median survival, 25 days; P = 0.0001). Median survival for the control group (n = 
      8) was 23.5 days. Moreover, there was no physical, behavioral, or pathological 
      evidence of treatment-related toxicity. These findings suggest that O6-BG can 
      potentiate the effects of interstitially delivered BCNU and, for tumors 
      expressing significant AGT, may be necessary for the BCNU to provide a meaningful 
      therapeutic benefit. Given the clinical use of BCNU polymers against malignant 
      gliomas, concurrent treatment with O6-BG may provide an important addition to our 
      therapeutic armamentarium.
FAU - Rhines, L D
AU  - Rhines LD
AD  - Department of Neurological Surgery, Johns Hopkins School of Medicine, Baltimore, 
      Maryland 21205, USA.
FAU - Sampath, P
AU  - Sampath P
FAU - Dolan, M E
AU  - Dolan ME
FAU - Tyler, B M
AU  - Tyler BM
FAU - Brem, H
AU  - Brem H
FAU - Weingart, J
AU  - Weingart J
LA  - eng
GR  - CA-09574/CA/NCI NIH HHS/United States
GR  - UO1-CA52857/CA/NCI NIH HHS/United States
GR  - UO1-CA57725/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Drug Implants)
RN  - 0 (Enzyme Inhibitors)
RN  - 01KC87F8FE (O(6)-benzylguanine)
RN  - 5Z93L87A1R (Guanine)
RN  - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase)
RN  - U68WG3173Y (Carmustine)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Alkylating/administration & dosage/*pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & 
      dosage/*pharmacology
MH  - Brain Neoplasms/*drug therapy/enzymology
MH  - Carmustine/administration & dosage/*pharmacology
MH  - Drug Implants
MH  - Drug Synergism
MH  - Enzyme Inhibitors/administration & dosage/*pharmacology
MH  - Glioma/*drug therapy/enzymology
MH  - Gliosarcoma/drug therapy/enzymology
MH  - Guanine/administration & dosage/*analogs & derivatives/*pharmacology
MH  - Humans
MH  - Male
MH  - Medulloblastoma/drug therapy/enzymology
MH  - O(6)-Methylguanine-DNA Methyltransferase/antagonists & inhibitors/metabolism
MH  - Rats
MH  - Rats, Inbred F344
MH  - Stereotaxic Techniques
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
EDAT- 2000/12/05 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/12/05 11:00
PHST- 2000/12/05 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/12/05 11:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2000 Nov 15;60(22):6307-10.