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Formation of DNA adducts and tumor growth delay following intratumoral administration of DTI-015

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Abstract

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.

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Authors and Affiliations

  1. Laboratory of Molecular Therapeutics, Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, CA

    William J. Bodell & Donald D. Giannini

  2. OncoPharmaceuticals, Inc., San Jose, CA

    Saira Singh

  3. Direct Therapeutics, Inc., Redwood City, CA

    Dennis Pietronigro

  4. Department of Neuro-Oncology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX, USA

    Victor A. Levin

Authors
  1. William J. Bodell
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  2. Donald D. Giannini
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  3. Saira Singh
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  4. Dennis Pietronigro
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  5. Victor A. Levin
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Bodell, W.J., Giannini, D.D., Singh, S. et al. Formation of DNA adducts and tumor growth delay following intratumoral administration of DTI-015. J Neurooncol 62, 251–258 (2003). https://doi.org/10.1023/A:1023383717833

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