Use of chemotherapeutic agents to induce cytotoxic DNA damage and programmed cell death is a key strategy in
cancer treatments. However, the 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 resulted in formation of abasic or apurinic/apyrimidinic (AP) sites, and blockage of AP sites led to a significant enhancement of
drug sensitivity due to reduction of
DNA base excision repair. Since a number of chemotherapeutic agents also induce formation of AP sites, monitoring of these sites as a clinical correlate of
drug effect will provide a useful tool in the development of
DNA-targeted
chemotherapies aimed at blocking abasic sites from repair. Here we report an imaging technique based on positron emission tomography (PET) that allows for direct quantification of AP sites in vivo. For this purpose, positron-emitting
carbon-11 has been incorporated into
methoxyamine ([(11)C]MX) that binds covalently to AP sites with high specificity. The binding specificity of [(11)C]MX for AP sites was demonstrated by in vivo blocking experiments. Using [(11)C]MX as a radiotracer, animal PET studies have been conducted in
melanoma and
glioma xenografts for quantification of AP sites. Following induction of AP sites by
temozolomide, both
tumor models showed significant increase of [(11)C]MX uptake in
tumor regions in terms of radioactivity concentration as a function of time, which correlates well with conventional
aldehyde reactive probe (ARP)-based bioassays for AP sites.