Developing cancer chemotherapeutics with enhanced selectivity is a major goal in cancer drug design. Several cancers, like acute myeloid leukemia, are known to possess an elevated reactive oxygen species phenotype. With this in mind, we designed and synthesized novel anti-cancer agent pro-drugs that are converted to reactive molecules upon oxidation by ROS. Our novel agent has been shown to be selective, with over 100-fold differences in the cytotoxicity in different cancer cells and normal, primary fibroblast cells. Early experiments in our lab have shown that the novel agents can react with nucleotides yielding an additional of a phenol on the rings of guanine, adenine, and cytosine. Primer extension experiments revealed the replication blocks from our agent. To confirm the mechanism of action we were interested in looking at the activation of DNA damage repair machinery inside the cells. Control experiments using HOGG-1, a base excision repair protein show no change in protein concentration, while nucleotide excision repair is activated. This shows the specific activation of DNA repair by our agent, which confirms our hypothesis, that the addition of a bulky molecule by our agent into the cellular DNA.

Biochemistry of the cellular response to the ROS activated anticancer agent

248th National Meeting (2014)

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