Enhanced radiosensitivity of androgen-resistant prostate cancer: AZD1152-mediated Aurora kinase B inhibition.

Aurora kinase B (AURKB) is critical to the process of mitosis, aiding in chromosome condensation by phosphorylating histone H3. We investigated the effects of AZD1152, an AURKB inhibitor, on radiosensitivity of androgen-insensitive prostate cancer cells. The goal of this study was to test whether AZD1152 increases the susceptibility of hormone-refractory prostate cancer cells to radiation-induced DNA damage and to determine the conditions of AZD1152 treatment that maximize radiosensitization. PC3 and DU145 cells were treated with various AZD1152 doses for various durations to elucidate the conditions that yielded maximal increases in G(2)/M-phase and polyploid cells. To assess DNA damage, γ-H2AX phosphorylation was quantified for cells grown under radiosensitizing conditions and subjected to either no radiation or 5 Gy radiation. Radiosensitivity was determined by clonogenic assays. Cell cycle effects in both cell lines were maximized by treatment with 60 nM AZD1152 for 48 h. AZD1152-treated cells exhibited significantly increased DNA damage 30 min postirradiation (PC3: 100% compared to 68%, P  =  0.035; DU145: 100% compared to 69%, P  =  0.034), with additional DNA damage 6 h postirradiation (PC3: 85% compared to 15%, P  =  0.002; DU145: 67% compared to 21%, P  =  0.012). Radiosensitivity was increased in both cell lines, with dose enhancement ratios of 1.53 for PC3 cells (P  =  0.017) and 1.71 for DU145 cells (P  =  0.02). This study identifies the optimal AZD1152 treatment conditions to maximize the radiosensitization of PC3 and DU145 cells. These results suggest a major role for DNA damage and impairment of DNA repair mechanisms in AZD1152-induced radiosensitization of prostate cancer cells.

Chemoradiotherapy in locally advanced, unresectable non-small cell lung cancer.

Chemoradiation is the major treatment option in unresectable, locally advanced non-small cell lung cancer. Many clinical trials have evaluated the efficacy of different combinations of chemotherapy and radiotherapy in this heterogeneous patient population. Early clinical trials showed a survival advantage of sequential chemo-RT compared to radiation alone. Subsequent trials demonstrated that concurrent chemo-RT improved survival over sequential chemo-RT. More recent studies have suggested that there is no advantage to adding induction chemotherapy prior to concurrent chemo-RT, or to adding consolidation chemotherapy after concurrent chemo-RT. Various clinical trials have used different chemotherapy regimens, though there is still no consensus about those which are most effective. Additionally, different radiotherapeutic strategies have included hyperfractionation vs. standard fractionation, use of 3-dimensional techniques, and altering total radiation dose. As these methods are being perfected, much attention has turned toward the use of molecularly targeted therapies. This review summarizes recent clinical trials examining the role of chemo-RT in locally advanced non-small cell lung cancer and the movement toward personalized medicine.