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Formation of DNA adducts
and tumor growth delay following intratumoral administration of DTI-015
William J. Bodell^, Donald
D. Giannini^,
Saira Singh*,
Dennis
Pietronigro+, Victor A. Levin°
^Laboratory
of Molecular Therapeutics, Department of Neurological Surgery, Brain Tumor
Research Center, University of California, San Francisco, CA;
*OncoPharmaceuticals, Inc., San Jose, CA;
+Direct Therapeutics, Inc., Redwood City, CA;
°Department of Neuro-Oncology, M.D. Anderson Cancer Center, The University of
Texas, Houston, TX, USA.
Intratumoral
(IT) administration of DTI-015 (BCNU in 100% ethanol) utilizes solvent
facilitated perfusion for the treatment of tumors.
RIF-1 tumors were treated by IT injection of either ethanol alone or 0.05–1.0
mg of DTI-015 or by iv injection of 0.5 mg
of BCNU.
Treatment with ethanol alone or iv injection of 0.5 mg
of BCNU did not produce a significant growth delay.
In contrast, IT administration of DTI-015 produced a significant growth delay at
each of the treatment doses (p < 0.05 to p < 0.001).
We have quantified the levels of N7-(2-hydroxyethyl) guanine (N7-HOEtG) in RIF-1
tumors 24 h following either IT treatment with
0.5 mg DTI-015 or ip administration of 0.5
mg BCNU.
Levels of N7-HOEtG (μmol/mol DNA) were ≤0.08 for both
untreated controls and following ip treatment with BCNU and 13.1 ±
5.6 following IT administration of DTI-015.
The levels of N7-HOEtG detected in RIF-1 tumors following IT administration of
DTI-015 were 164-fold higher than the level(s) of N7-HOEtG in the ip BCNU
treated tumor samples.
These studies demonstrate that IT administration of DTI-015 produces high levels
of DNA adducts in the tumor which correspond to a significant increase in tumor
growth delay compared to the same dose of BCNU administered systemically.
Copyright ©
2003 Kluwer Academic Publishers.
All rights reserved
Source: http://www.kluweronline.com/issn/0167-594X/contents
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