Abstract
1558
Objectives To directly quantify abasic or apurinic/apyrimidinic (AP) sites induced by DNA-targeted chemotherapeutic agents. Efficacy of DNA-targeted agents such as temozolomide is often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway results in formation of AP sites and inhibition of AP sites leads to significant reduction of drug resistance and enhancement of drug sensitivity. Thus, AP-site formation has been identified as an important biomarker in DNA-targeted chemotherapies.
Methods Design, synthesis, and evaluation of PET imaging agents that bind to AP sites with high affinity and specificity. To date, we have developed [11C] methoxyamine (MX) for PET that allows for quantification of AP sites in vivo.
Results [11C] MX has been synthesized with high radiochemical yield and purity. MicroPET studies have been conducted to evaluate their pharmacokinetic profiles in melanoma and glioma xenograft tumor mouse models that are pre-treated with temozolomide to induce AP-site formation. Subsequent quantitative analysis showed that the radioactivity concentration were elevated in proportion to the AP sites induced in tumor regions pre-treated with temozolomide relative to tumor regions without any treatment. In vivo blocking studies based on microPET also showed that the agents bound to AP sites with high specificity.
Conclusions Our studies demonstrated that PET imaging can be used to monitor DNA damages and repair and evaluate efficacy of DNA-targeted therapeutic treatments in cancer.
- © 2009 by Society of Nuclear Medicine