Cytosine-based nucleoside analogs are selectively lethal to DNA mismatch repair-deficient tumour cells by enhancing levels of intracellular oxidative stress.
BACKGROUND
DNA mismatch repair deficiency is present in a significant proportion of a number of solid tumours and is associated with distinct clinical behaviour.


METHODS
To identify the therapeutic agents that might show selectivity for mismatch repair-deficient tumour cells, we screened a pair of isogenic MLH1-deficient and MLH1-proficient tumour cell lines with a library of clinically used drugs. To test the generality of hits in the screen, selective agents were retested in cells deficient in the MSH2 mismatch repair gene.


RESULTS
We identified cytarabine and other related cytosine-based nucleoside analogues as being selectively toxic to MLH1 and MSH2-deficient tumour cells. The selective cytotoxicity we observed was likely caused by increased levels of cellular oxidative stress, as it could be abrogated by antioxidants.


CONCLUSIONS
We propose that cytarabine-based chemotherapy regimens may represent a tumour-selective treatment strategy for mismatch repair-deficient cancers.
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK.
M
M
Hewish
S A
SA
Martin
R
R
Elliott
D
D
Cunningham
C J
CJ
Lord
A
A
Ashworth
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology*; D053843:DNA Mismatch Repair / Q000187:drug effects*; D049914:DNA Repair-Deficiency Disorders / Q000188:drug therapy*; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D009705:Nucleosides; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D009705:Nucleosides; D003561:Cytarabine; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein