Malignant gliomas have an extremely poor prognosis with median survival rates of less than 2 years. Although most frequent in older adults, these tumors are the third leading cause of cancer deaths in persons 15 to 34 years of age. Alkylating agents, used in single agent or combination chemotherapy with surgery and radiation, are the most effective antitumor drugs for treatment of adult gliomas. However, intrinsic and acquired resistance limits their usefulness. Our broad, long term objective is to define the contribution of DNA repair mechanisms to glioma resistance to chemotherapeutic alkylating agents, and to identify strategies to combat resistance. We have shown that resistance of human gliomas to alkylating agents is based on a mechanism(s) in addition to the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Our overall hypothesis is that apurinic/apyrimidinic endonuclease (Ap endo), a DNA repair activity that removes cytotoxic, alkylation-induced abasic sites, contributes to human glioma alkylating agent resistance. Our preliminary data show that gliomagenesis is accompanied by elevation of Ap endo activity, and that activity is positively correlated with tumor characteristics associated with poor prognosis. To address our hypothesis, we will [1] determine the contribution of Ap endo to alkylator resistance in glioma cell with different DNA repair backgrounds, [2] determine the effects of endogenous oxidative stress on Ap endo activity and alkylator resistance, and [3] characterize the oxidative free radical-induced elevation of Ap endo and enhanced alkylator resistance that we have recently observed in human glioma cells. The latter studies may be significant for design of optimal alkylating agent protocols, especially when employed concurrently with radiotherapy. We will also [4] examine the relationship of activity with response to alkylating agent-based chemotherapy (time to tumor progression). Evidence for a contribution of Ap endo to resistance would identify a new target for anti-resistance strategies directed against Ape1/Ref-1 (the major human Ap endo), either alone or together with MGMT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104593-05
Application #
7458612
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2004-09-23
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
5
Fiscal Year
2008
Total Cost
$283,597
Indirect Cost
Name
University of Washington
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bobola, Michael S; Alnoor, Mohammad; Chen, John Y-S et al. (2015) O(6)-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma. BBA Clin 3:1-10
Silber, John R; Bobola, Michael S; Blank, A et al. (2012) O(6)-methylguanine-DNA methyltransferase in glioma therapy: promise and problems. Biochim Biophys Acta 1826:71-82
Bobola, Michael S; Kolstoe, Douglas D; Blank, A et al. (2012) Repair of 3-methyladenine and abasic sites by base excision repair mediates glioblastoma resistance to temozolomide. Front Oncol 2:176
Bobola, Michael S; Jankowski, Pawel P; Gross, Mary E et al. (2011) Apurinic/apyrimidinic endonuclease is inversely associated with response to radiotherapy in pediatric ependymoma. Int J Cancer 129:2370-9
Bobola, Michael S; Kolstoe, Douglas D; Blank, A et al. (2010) Minimally cytotoxic doses of temozolomide produce radiosensitization in human glioblastoma cells regardless of MGMT expression. Mol Cancer Ther 9:1208-18
Bobola, Michael S; Blank, A; Berger, Mitchel S et al. (2007) O6-methylguanine-DNA methyltransferase deficiency in developing brain: implications for brain tumorigenesis. DNA Repair (Amst) 6:1127-33
Bobola, Michael S; Varadarajan, Sridhar; Smith, Nolan W et al. (2007) Human glioma cell sensitivity to the sequence-specific alkylating agent methyl-lexitropsin. Clin Cancer Res 13:612-20
Bobola, Michael S; Finn, Laura S; Ellenbogen, Richard G et al. (2005) Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors. Clin Cancer Res 11:7405-14