|
|
|
|
|
|
||
|
|
||||
|
|
||||
|
||||
Preclinical Experimental Therapeutics |
Brain Tumor Research Center of the Department of Neurological Surgery, University of California, San Francisco, CA 94143-0555 (W.J.B., D.D.G.); Department of Neurosurgery (S.H.) and Department of Neuro-Oncology (V.A.L.), The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
2 Address correspondence and reprint requests to William J. Bodell, University of California, Box-0555, San Francisco, CA 94143-0555.
Abstract
The level of N7-(2-hydroxyethyl)guanine (N7-HOEtG), one of the DNA alkylation products formed by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment, was measured in human brain tumor samples by high performance liquid chromatography with electrochemical detection. The tumors from 6 recurrent chemotherapy-naïve patients with recurrent glioblastoma multiforme were analyzed as controls. The mean level of N7-HOEtG in DNA of these specimens was 0.42 pmol/mg DNA. Samples were also obtained from a patient with a recurrent glioblastoma multiforme after direct intratumoral therapy with BCNU in ethanol (DTI-015). The levels of N7-HOEtG in the samples distal, medial, and adjacent to the site of injection were 0.8, 2.6, and 369.5 pmol/mg DNA, respectively. Comparison of the level of N7-HOEtG detected in the distal sample after injection with BCNU in ethanol with the mean level of the untreated samples indicated that it was not sufficiently different to be ruled out as a chance occurrence. Comparison of the levels of N7-HOEtG in the medial and adjacent brain tumor samples with the mean level of the control samples showed values that were approximately 6- and 879-fold higher. These results demonstrate that intratumoral administration of BCNU in ethanol produces significant levels of DNA alkylation and suggest that DNA adduct measurements provide a unique molecular dosimeter to evaluate delivery of alkylating agents to brain tumors.
References
Belanich, M., Pastor M., Randall, T., Guerra, D., Kibitel, J.,
Alas, L., Li, B., Citron, M., Wasserman, P., White, A., Eyre, H., Jaeckle, K.,
Schulman, S., Rector, D., Prados, M., Coons, S., Shapiro, W., and Yarosh, D.
(1996) Retrospective study of the correlation between the DNA
repair protein alkyltransferase and survival of brain tumor patients treated
with carmustine. Cancer Res.
56,783
-788.
Bodell, W.J. (1990) Molecular dosimetry for sister chromatid exchange induction and cytotoxicity by monofunctional and bifunctional alkylating agents. Mutat. Res. 233,203 -210.[CrossRef][ISI][Medline]
Bodell, W.J. (1999) Effect of cations on the formation of DNA alkylation products in DNA reacted with 1-(2-chloroethyl)-1-nitrosourea. Chem. Res. Toxicol. 12,965 -970.[CrossRef][ISI][Medline]
Bodell, W.J., Tokuda, K., and Ludlum, D.B. (1988)
Differences in DNA alkylation products formed in sensitive and resistant
glioma cells treated with N-(2-chloroethyl)-N-nitrosourea. Cancer
Res. 48,4489
-4492.
Brem, H., Ewend, M.G., Piantadosi, S., Greenhoot, J., Burger, P.C., and Sisti, M. (1995) The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: Phase I trial. J. Neurooncol. 26,111 -123.[CrossRef][Medline]
Dolan, M.E., and Pegg, A.E. (1997) O6-benzylguanine and its role in chemotherapy. Clin. Cancer Res. 3,837 -847.[Abstract]
Filser, J.G., Denk, B., Törnqvist, M., Kessler, W., and Ehrenberg, L. (1992) Pharmacokinetics of ethylene in man: Body burden with ethylene oxide and hydroxyethylation of hemoglobin due to endogenous and environmental ethylene. Arch. Toxicol. 66,157 -163.[CrossRef][ISI][Medline]
Friedman, H.S., Kokkinakis, D.M., Pluda, J., Friedman, A.H., Cokgor, I., Haglund, M.M., Ashley, D.M., Rich, J., Dolan, M.E., Pegg, A.E., Moschel, R.C., McLendon, R.E., Kerby, T., Herndon, J.E., Bigner, D.D., and Schold, S.C., Jr. (1998) Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma. J. Clin. Oncol. 16,3570 -3575.[Abstract]
Jaeckle, K.A., Eyre, H.J., Townsend, J.J., Schulman, S., Knudson, H.M., Belanich, M., Yarosh, D.B., Bearman, S.I., Giroux, D.J., and Schold, S.C., Jr. (1998) Correlation of tumor O6-methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: A Southwest Oncology Group study. J. Clin. Oncol. 16,3310 -3315.[Abstract]
Kleihues, P., and Cavenee, W.K. (1997) Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency fo Research on Cancer. pp. 1-9.
Lamborn, K.R., Prados, M.D., Kaplan, S.B., and Davis, R.L. (1999) Final report on the University of California-San Francisco experience with bromode-oxyuridine labeling index as a prognostic factor for the survival of glioma patients. Cancer 85,925 -935.[CrossRef][ISI][Medline]
Levin, V.A., and Prados, M.D. (1992) Treatment of
recurrent gliomas and metastatic brain tumors with a polydrug protocol
designed to combat nitrosourea resistance. J. Clin.
Oncol. 10,766
-771.
Levin, V.A., Kabra, P.A., and Freeman-Dove, M.A. (1978) Relationship of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclo-hexyl-1-nitrosourea (CCNU) pharmacokinetics of uptake, distribution, and tissue/plasma partitioning in rat organs and intracerebral tumors. Cancer Chemother. Pharmacol. 1,233 -242.[ISI][Medline]
Levin, V.A, Patlak, C.S, and Landahl, H.D. (1980) Heuristic modeling of drug delivery to malignant brain tumors. J. Pharmacokinet. Biopharm. 8,257 -296.[CrossRef][ISI][Medline]
Ludlum, D.B. (1990) DNA alkylation by the haloethylnitrosoureas: Nature of modifications produced and their enzymatic repair or removal. Mutat. Res. 233,117 -126.[CrossRef][ISI][Medline]
Mahaley, M.S., Jr. (1991) Neuro-oncolgy index and review (adult primary brain tumors): Radiotherapy, chemotherapy, immunotherapy, photodynamic therapy. J. Neurooncol. 11, 85-147.[CrossRef][Medline]
Nagane, M., Coufal, F., Lin, H., Bogler, O., Cavenee, W.K., and
Huang, H.-J.S. (1996) A common mutant epidermal growth factor
receptor confers enhanced tumorigenicity on human glioblastoma cells by
increasing proliferation and reducing apoptosis. Cancer
Res. 56,5079
-5086.
Pietronigro, D., Drnovsky, F., Cravioto, H., and Ransohoff, J. (1999) Stereotactic intratumoral injection of DTI-015 in a rat intracranial T9 gliosarcoma model. Proc. Am. Assoc. Cancer Res. 40,583 . (Abstract)
Rogers, L.R., Purvis, J.B., Lederman, R.J., Rosenbloom, S.A., Tomsak, R.L., Estes, M.L., Magdinec, M., Medendorp, S.V., and Boyett, J.M. (1991) Alternating sequential intracarotid BCNU and cisplatin in recurrent malignant glioma. Cancer 68, 15-21.[CrossRef][ISI][Medline]
Schold, S.C., Jr., Kuhn, J.G., Chang, S.M., Bosik, M.E., Robins, H.I., Mehta, M.P., Spence, A.M., Fulton, D., Fink, K.L., and Prados, M.D. (2000) A phase I trial of 1,3 bis(2-chloroethyl)-1-nitrosourea plus temozolomide: A North American Brain Consortium study. Neuro-Oncology. [serial online], Doc. 99-26, December 9, 1999. URL http://neuro-oncology.mc.duke.edu Neuro-Oncol. 2,34 -39.[Abstract]
Wu, K.-Y., Scheller, N., Ranasinghe, A., Yen, T.-Y., Sangaiah, R., Giese, R., and Swenberg, J.A. (1999) A gas chromatography/electron capture/negative chemical ionization high-resolution mass spectrometry method for analysis of endogenous and exogenous N7-(2-hydroxyethyl)guanine in rodents and its potential for human biological monitoring. Chem. Res. Toxicol. 12,722 -729.[CrossRef][ISI][Medline]
Ye, Q., and Bodell, W.J. (1997) Detection of N7-(2-hydroxyethyl)guanine adducts in DNA and 9L cells treated with 1-(2-chloroethyl)-1-nitrosourea. J. Chromatogr. B. Biomed. Sci. Appl. 694,65 -70.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  W. J. Bodell, A. P. Bodell, and D. D. Giannini Levels and distribution of BCNU in GBM tumors following intratumoral injection of DTI-015 (BCNU-ethanol) Neuro-oncol, January 1, 2007; 9(1): 12 - 19. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Hall, B. A. Moffat, J. Stojanovska, T. D. Johnson, Z. Li, D. A. Hamstra, A. Rehemtulla, T. L. Chenevert, J. Carter, D. Pietronigro, et al. Therapeutic Efficacy of DTI-015 using Diffusion Magnetic Resonance Imaging as an Early Surrogate Marker Clin. Cancer Res., December 1, 2004; 10(23): 7852 - 7859. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
