Abstract

The clinical studies outlined in this specific aim target the manipulation of 06-methylguanine DNA methyltransferase (MGMT) in humans and are the result of extensive pre-clinical work demonstrating the efficacy of the approaches in animal models. One project proposes to increase the expression of MGMT in hematopoietic cells in an effort to diminish the cumulative myelosuppression commonly encountered with chloroethylnitrosoureas (CENUs). This project utilizes a recombinant retroviral vector extensively tested in murine studies and produced by the National Gene Vector Laboratory at Indiana University for human clinical trials. The clinical study builds on a current pilot study at Indiana University, designed by Dr. Regina Jakacki and supported in part by NCI funding, which utilities peripheral blood stem-progenitor cell infusions to decrease hematopoietic toxicities and allow schedule compression of an extensively used brain treatment protocol called """"""""PCV"""""""" (procarbazine, CCNU, vincristine). The second project is designed to diminish expression of MGMT in tumor cells. Based on pre-clinical work by Dr. Leonard Erickson, MGMT can be effectively depleted from tumor cell lines by the sequential treatment with agents that produce the natural substrate for MGMT, 06-methylguanine, or act as a substrate for MGMT directly. One such agent, 06-benzylguanine (6-BG), is currently in phase I trials at other institutions.
The specific aims of the study are: 1) To conduct a pilot study of dose-intensified procarbazine, CCNU, vincristine (PCV) for poor prognosis pediatric and adult brain tumor utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with 06-methylguanine DNA methyltransferase (MGMT). 2) To conduct a phase I trial to determine the toxicity of the combination of 06-benzylguanine and BCNU, and to examine the inhibition of MGMT activity in tumor biopsies in patients treated with this combination chemotherapy for relapsed B cell malignancies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA075426-05
Application #
6563891
Study Section
Project Start
2002-03-01
Project End
2003-02-28
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
5
Fiscal Year
2002
Total Cost
$220,099
Indirect Cost

  Institution

Name
Indiana University-Purdue University at Indianapolis
Department
Type
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202

  Publications

Hegde, Vijay; Wang, Mu; Deutsch, Walter A (2004) Human ribosomal protein S3 interacts with DNA base excision repair proteins hAPE/Ref-1 and hOGG1. Biochemistry 43:14211-7
Hegde, Vijay; Wang, Mu; Deutsch, Walter A (2004) Characterization of human ribosomal protein S3 binding to 7,8-dihydro-8-oxoguanine and abasic sites by surface plasmon resonance. DNA Repair (Amst) 3:121-6
Fishel, Melissa L; Seo, Young R; Smith, Martin L et al. (2003) Imbalancing the DNA base excision repair pathway in the mitochondria; targeting and overexpressing N-methylpurine DNA glycosylase in mitochondria leads to enhanced cell killing. Cancer Res 63:608-15
Kreklau, Emiko L; Pollok, Karen E; Bailey, Barbara J et al. (2003) Hematopoietic expression of O(6)-methylguanine DNA methyltransferase-P140K allows intensive treatment of human glioma xenografts with combination O(6)-benzylguanine and 1,3-bis-(2-chloroethyl)-1-nitrosourea. Mol Cancer Ther 2:1321-9
Roth, Timothy J; Xu, Yi; Luo, Meihua et al. (2003) Human-yeast chimeric repair protein protects mammalian cells against alkylating agents: enhancement of MGMT protection. Cancer Gene Ther 10:603-10
Wu, M; Pasula, R; Smith, P A et al. (2003) Mapping alveolar binding sites in vivo using phage peptide libraries. Gene Ther 10:1429-36
Kelley, Mark R; Kow, Yoke W; Wilson 3rd, David M (2003) Disparity between DNA base excision repair in yeast and mammals: translational implications. Cancer Res 63:549-54
Dobson, Allison W; Grishko, Valentina; LeDoux, Susan P et al. (2002) Enhanced mtDNA repair capacity protects pulmonary artery endothelial cells from oxidant-mediated death. Am J Physiol Lung Cell Mol Physiol 283:L205-10
He, Ying-Hui; Xu, Yi; Kobune, Masayoshi et al. (2002) Escherichia coli FPG and human OGG1 reduce DNA damage and cytotoxicity by BCNU in human lung cells. Am J Physiol Lung Cell Mol Physiol 282:L50-5
Wu, Min; He, Ying-Hui; Kobune, Masayoshi et al. (2002) Protection of human lung cells against hyperoxia using the DNA base excision repair genes hOgg1 and Fpg. Am J Respir Crit Care Med 166:192-9

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