Dianhydrogalactitol induces replication-dependent DNA damage in tumor cells preferentially resolved by homologous recombination.

ABSTRACT: 1,2:5,6-Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent causing N⁷-guanine alkylation and inter-strand DNA crosslinks currently in clinical trial for treatment of glioblastoma. While preclinical studies and clinical trials have demonstrated antitumor activity of DAG in a variety of malignancies, understanding the molecular mechanisms underlying DAG-induced cytotoxicity is essential for proper clinical qualification. Using non-small cell lung cancer (NSCLC) as a model system, we show that DAG-induced cytotoxicity materializes when cells enter S phase with unrepaired N⁷-guanine DNA crosslinks. In S phase, DAG-mediated DNA crosslink lesions translated into replication-dependent DNA double-strand breaks (DSBs) that subsequently triggered irreversible cell

SUBMITTER: Zhai B 

PROVIDER: S-EPMC6170372 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature