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Quinacrine, a 9-aminoacridine derivative, is an old antimalarial drug which was widely prescribed to humans until it was superceded by chloroquine. We have reported previously that quinacrine is a powerful activator of p53 and an inhibitor of NF-κB and thereby inducing cell death through apoptosis in a number of human cell lines representing a large variety of cancer types. Of note, it has been previously reported that quinacrine appears to inhibit the repair of radiation induced DNA single strand breaks in both prokaryotic and eukaryotic experimental systems. These data supported the initiation of an ongoing phase II clinical trial of quinacrine as an anticancer agent. We now hypothesize that quinacrine-induced radiation sensitization, as well as inhibition of single strand DNA repair following irradiation, may be dependent on p53 and NF-κB pathways. Furthermore, since many cancer cells are known to constitutively over-express NF-κB which mediates p53 suppression, quinacrine may act as a cancer specific radiation sensitizer. To test our hypothesis, we are investigating the interaction of quinacrine and radiation on a panel of human cancer cell lines (HCT116, HT1080, and RCC45 - colon carcinoma, fibrosarcoma, and renal cell carcinoma, respectively) expressing functional p53 protein, as well as their isogenic p53 non-expressing variants using a standard colony formation assay as well as a proliferation assay. Our preliminary results show that all three p53 expressing cell lines are more sensitive to radiation alone as well as quinacrine alone compared to their respective p53 non-expressing counterparts. Also, we have found that quinacrine does in fact enhance the efficacy of radiation, acting in a synergistic manner, in cells expressing p53. Our group has recently found that one of enantiomers of quinacrine, (R)-quinacrine, is more potent than (S)-quinacrine, as well as the racemic mixture in inhibiting NF-κB and activating p53. Relative radiosensitizing efficacy of a racemic mixture as well as a pure isomeric (R)- or (S)- quinacrine in vitro and in mouse xenograft models, will be presented.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA