Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed. Aspects including measurement strategies, identification of adducts, and biological factors that influence the predictive relationship between DNA modification and biological response are addressed. A positive correlation between DNA adduct levels and response was observed for the majority of the studies, demonstrating the high potential of using DNA adducts from anticancer drugs as mechanism-based biomarkers of susceptibility, especially as bioanalysis approaches with higher sensitivity and throughput emerge.
Bibliographical noteFunding Information:
*E-mail: firstname.lastname@example.org. ORCID Alessia Stornetta: 0000-0002-8287-9551 Funding This work was supported by the European Research Council (260341 and 680920), the Swiss National Science Foundation (156280 and 152621), the ETH research commission (ETH-43 14-1), NIH grants CA93373, SBIR contracts to AMD Phase I HHSN261201000133C, Phase II HHSN261201200048C, LLNL grants LDRD 08-LW-100, NIH/NIGMS P41 RR13461, the American Cancer Society, and the Knapp Family Fund. Work was performed (partially) at the Research Resource for Biomedical AMS, which is operated at LLNL under the auspices of the U.S. Department of Energy under contract DE-AC52-07NA27344. The Research Resource is supported by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program grant P41 RR13461. Notes The authors declare no competing financial interest. Biographies Alessia Stornetta was born in Bellinzona, in the Italian-speaking region of Switzerland. She completed her B.S. degree (2010) and M.S. degree (2012) at the ETH Zurich, the Swiss Federal Institute of Technology in Zurich, Switzerland. She has carried out doctoral
© 2016 American Chemical Society.