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Treatment
> Carmustine
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Neuro-oncol 2006,
Epub 2006 Oct 3. DOI:10.1215/15228517-2006-014
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Abstract |
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Levels and distribution of BCNU in GBM
tumors following intratumoral injection of DTI-015 (BCNU-ethanol)
William J. Bodell1*,
Alexander P. Bodell1,
Donald D. Giannini1
1Laboratory of Molecular
Therapeutics, Brain Tumor Research Center, Department of Neurological
Surgery, University of California, San Francisco, CA 94143 . -- *
To whom correspondence should be addressed. E-mail: williamjbodell@yahoo.com.
-- Received October 8, 2005. Accepted May 12, 2006.
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The alkylation products formed by in vitro
treatment of DNA with tritium-labeled
1,3-bis(2-chloroethyl)-1-nitrosourea (3H-BCNU) were
identified and quantified.
Twelve adducts were resolved by
high-performance liquid chromatography (HPLC).
The principal DNA adducts
formed by BCNU treatment corresponded to N-7-(2-hydroxyethyl)guanine
(N7-HOEtG) (26%), N-7-(2-chloroethyl)guanine (15%), and
phosphotriesters (19%).
In addition, several minor products were
identified as 1,2-(diguan-7-yl)ethane, N-1-(2-hydroxyethyl)-2-deoxyguanosine,
1‑(N-1-2-deoxyguanosinyl), 2-(N-3-2-deoxycytidyl)ethane
cross-link, and O-6-(2-hydroxyethyl)-2-deoxyguanosine,
and individually they represented 1% to 5% of the total
alkylation.
An HPLC-electron capture method
was applied to quantify the levels of N7-HOEtG in samples
treated with BCNU.
Treatment of either purified DNA or
U87MG cells with various amounts of BCNU produced a linear increase
in the amount of N7-HOEtG.
These results demonstrated that
the levels of N7-HOEtG formed by BCNU treatment could be used
as a molecular dosimeter of BCNU treatment dose.
We measured the levels of
N7-HOEtG in DNA isolated from tumor samples taken from four
patients with GBM tumors following stereotactic intratumoral injection
with DTI-015 (BCNU-ethanol).
The level of N7-HOEtG in these
samples ranged from 14.7 to 121.9 µmol N7-HOETG/mol DNA
within 1 cm of the site of injection.
As the distance from the site
of injection increased, the levels of N7-HOEtG in tumor DNA
decreased.
In two of the samples, the levels of
N7-HOEtG were 0.2 to 0.3 µmol N7-HOETG/mol DNA at 3.5 to
3.9 cm from the site of injection, demonstrating
significant distribution of BCNU in the tumor.
The levels of N7-HOEtG in these tumor
samples corresponded to BCNU treatment concentrations of 0.02
to 43.0 mM.
These studies demonstrate that
stereotactic intratumoral injection of DTI-015 into human
GBM tumors produces high concentrations of BCNU up to 2.5
cm from the site of injection in some of the tumors.
These observations suggest that
intratumoral injection of DTI-015 may be of benefit in the
treatment of primary and recurrent GBM tumors.
Key Words: BCNU, carmustine,
DTI-015, ethanol, glioblastoma multiforme, intratumoral
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© Copyright 2006 by the Society for
Neuro-Oncology
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.JPG)
Abstract
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