Prognostic value of survivin in locally advanced prostate cancer: study based on RTOG 8610.

PURPOSE: To examine the prognostic value of nuclear and cytoplasmic survivin expression in men with locally advanced prostate cancer who were enrolled in Radiation Therapy Oncology Group (RTOG) protocol 8610. METHODS AND MATERIALS: RTOG 8610 was a Phase III randomized study comparing the effect of radiotherapy plus short-term androgen deprivation with radiotherapy alone. Of the 456 eligible patients, 68 patients had suitably stained tumor material for nuclear survivin analysis and 65 patients for cytoplasmic survivin. RESULTS: Compared with patients with nuclear survivin intensity scores of 191.2 had significantly improved prostate cancer survival (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-1.00, p = 0.0452). On multivariate analysis, nuclear survivin intensity scores >191.2 were significantly associated with improved overall survival (HR, 0.46; 95% CI, 0.25-0.86; p = 0.0156) and prostate cancer survival (HR, 0.36; 95% CI, 0.16-0.84; p = 0.0173). On univariate analysis, compared with patients with cytoplasmic survivin integrated optical density 82.7 showed a significantly increased risk of local progression (HR, 2.49; 95% CI, 1.03-6.01; p = 0.0421). CONCLUSION: Nuclear overexpression of survivin was associated with improved overall and prostate cancer survival on multivariate analysis, and cytoplasmic overexpression of survivin was associated with increased rate of local progression on univariate analysis in patients with locally advanced prostate cancer treated on RTOG 8610. Our results might reflect the different functions of survivin and its splice variants, which are known to exist in distinct subcellular compartments.

State-of-the-art radiotherapy in the management of clinically localized prostate carcinoma.

Four Phase III trials demonstrating higher prostate-specific antigen control rates in prostate cancer patients treated with higher doses of radiation have changed the standard of care. Emerging on-line technologies, improved imaging and computer algorithms, combined with an improved understanding of how best to apply them, have allowed radiation oncologists to move ever closer to the optimal application of curative radiation. This technology allows a higher dose to be delivered to tumor-bearing areas while minimizing the dose delivered to surrounding normal tissues. Real-time adaptive techniques have made each step more accurate, and commercialization has increasingly moved these advances further into the community setting. Phase III trials have also helped to define the role of hormonal therapy in combination with radiation and the benefits of prophylactic pelvic nodal radiotherapy in subsets of patients. We have also learnt how to optimize the use of prostate-specific antigen to better determine success and failure following radiotherapy.

Adenovirus-mediated inhibition of survivin expression sensitizes human prostate cancer cells to paclitaxel in vitro and in vivo.

BACKGROUND: Improvements in the response rates to chemotherapy would represent an important advancement in the care of patients with metastatic prostate cancer. There is accumulating evidence that Survivin, a member of the inhibitor of apoptosis (IAP) family, is associated with both cancer progression and drug resistance. The purpose of this study is to investigate the role of Survivin in paclitaxel-resistance and whether the targeting of Survivin sensitizes prostate cancer cells to paclitaxel. METHODS: Human prostate cell lines PC-3, DU-145, and LNCaP were infected with replication-deficient adenoviruses encoding either wild-type Survivin [pAd-S(WT)], to examine Survivin overexpression effects, or a phosphorylation-defective Survivin Thr34 --> Ala dominant negative mutant [pAd-S(T34A)], to examine Survivin inactivation effects. The effects of wild-type or mutant Survivin on spontaneous and paclitaxel-induced apoptosis were investigated both in vitro and in vivo. RESULTS: Forced overexpression of wild-type Survivin with pAd-S(WT) increased resistance to paclitaxel in all cell lines, both in vitro and in vivo. Inhibition of Survivin using pAd-S(T34A) resulted in a significant increase in the rate of spontaneous and paclitaxel-induced apoptosis in all cell lines, both in vitro and in vivo. This effect was abolished by co-treatment with VAD-CHO (Calbiochem, San Diego, CA), a pan-caspase inhibitor, indicating that Survivin normally mediates resistance to paclitaxel through suppression of caspase-mediated apoptosis. CONCLUSIONS: Survivin mediates paclitaxel-resistance in prostate cancer cells. The inhibition of Survivin sensitizes prostate cancer cells to paclitaxel-induced apoptosis through a caspase-dependant mechanism in vitro and in vivo.