Article

DNA repair and cancer stem-like cells--potential partners in glioma drug resistance?

NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway.
Cancer Treatment Reviews (impact factor: 6.05). 06/2008; 34(6):558-67. DOI:10.1016/j.ctrv.2008.03.125 pp.558-67
Source: PubMed

ABSTRACT Glioblastoma is the most malignant and frequent primary brain tumour in adults. Current treatment remains insufficient as these tumours display a diffuse infiltrative growth pattern and tend to recur despite extensive debulking surgery followed by radio- and chemotherapy. The alkylating agents carmustine (1,3-bis-(2-chloroethyl)-1-nitrosourea, or BCNU) and temozolomide (TMZ) are the drugs of choice for adjuvant glioma chemotherapy. However, several independent DNA repair mechanisms can restore the integrity of alkylated DNA bases, and thus contribute to drug resistance and subsequent therapy failure. Recent work suggests that glioblastomas develop as cellular and functional hierarchies through small subpopulations of stem cell-like cancer cells that are responsible for tumour initiation and maintenance. Such cells also appear to possess enhanced DNA repair capacity compared to other cells within the tumours. Challenges in glioblastoma therapy are to determine (1) whether the cancer stem-like cell subpopulations represent a clinically novel target for therapy, and (2) which additional treatment strategies should be applied to improve quality of life and prolong survival of glioblastoma patients. This review addresses clinically relevant mechanisms which contribute to glioma resistance towards current alkylating agent-based chemotherapy, and discusses related mechanisms and treatment strategies in the light of the cancer stem cell hypothesis.

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Keywords

additional treatment strategies
 
adjuvant glioma chemotherapy
 
alkylated DNA bases
 
alkylating agents carmustine
 
cancer stem-like cell subpopulations
 
cell-like cancer cells
 
clinically novel target
 
current alkylating agent-based chemotherapy
 
diffuse infiltrative growth pattern
 
drug resistance
 
extensive debulking surgery
 
frequent primary brain tumour
 
functional hierarchies
 
glioblastoma patients
 
glioma resistance
 
review addresses clinically relevant mechanisms
 
small subpopulations
 
subsequent therapy failure
 
treatment strategies
 
tumours display
 

Tor-Christian Aase Johannessen