Ciência e terapia do câncer

In vivo Quantification of Abasic Sites for Efficacious Evaluation of DNA Targeted Chemotherapies

Abstract

Wenxia Zhu, Chunying Wu, Yuguo Li, Eduardo Somoza, Lili Liu, Stanton Gerson and Yanming Wang

DNA damage and repair represent important biological processes that are targets of various chemotherapies against cancer. In many ways, chemotherapeutic agents can induce DNA damage in cancerous as well as normal cells. However, DNA damage induced by chemotherapeutic agents can be intrinsically repaired by normal physiologic responses, which hampers inhibition of tumor growth and cause drug-resistance. Base excision repair (BER) is one such physiologic process that is important in the cellular response to many chemotherapeutic agents, specifically those agents that target DNAs. Once the BER pathway is triggered, damaged DNA bases undergo a series of chemical modifications resulting in the formation of abasic or apurinic/apyrimidinic (AP) site, which serves as key intermediates in the excision of damaged DNA bases and restoration of regular bases. To monitor BER- conferred intrinsic drug-resistance to chemotherapeutic agents such as DNA-alternating temozolomide (TMZ), pemetrexed (Alimta ® ), and fludarabine, we have developed a F-18 labeled fluoroethoxyamine ([ 11 C]FEX) as an imaging agent for positron emission tomography (PET) imaging of DNA damage and repair in vivo . In this work, we report the synthesis, radiolabeling, and evaluation of [ 18 F]FEX in vivo in mice. We have shown that [ 18 F]FEX- PET can be used to monitor DNA damage and repair in tumor xenograft mouse models including an uracil DNA glycosylase (UDG)-knockout tumor mouse model of non-small cell lung cancer (NSCLC).