UP-02.094Prospective Evaluation of SerumTriglyceride Concentration andProstate Cancer Risk in a MulticenterStudySalem S1,2, Mehrsai A1, Pourmand G1

1Urology Research Center, Sina Hospital,Tehran University of Medical Sciences,Tehran, Iran, 2Dept. of Urology, CaseWestern Reserve University, Cleveland,USA

Introduction and Objective: Serumlipid concentration as a part of the meta-bolic syndrome is supposed to be linkedto prostate cancer risk. However, few epi-demiological studies have assessed therelation between serum triglyceride leveland risk of prostate cancer. This studysought to further evaluate the probableassociation between serum triglyceridelevel and prostate cancer risk.Materials and Methods: Using data froma prospective hospital-based multi-centercase-control study, serum triglyceride con-centrations as well as thorough demo-graphic and medical characteristics weredetermined in 194 cases with the newlydiagnosed, clinicopathologically confirmedprostate cancer and 317 controls, withoutany malignant disease, admitted to thesame network of hospitals. Serum triglyc-eride levels were categorized into tertiles.Multivariate logistic regression model wasused to estimate odds ratios (OR) and cor-responding 95% confidence intervals (CI)after adjustment for major potential con-founders, including age, body mass index,smoking, alcohol, education, occupation,marital status, family history of prostatecancer and sex hormones level.Results: The mean (�SD) serum triglycer-ide level in case and control groups were146.56�99.68 mg/dl and 146.16�78.83mg/dl, respectively; the difference was notstatistically significant (P�0.96). After adjust-ment for the mentioned confounders, se-rum triglyceride concentration was not sig-nificantly associated with the increased riskof prostate cancer (OR: 1.02, 95% CI: 0.53-1.90; P�0.97, comparing the highest withthe lowest tertiles). Serum triglyceride wasstatistically correlated with serum total tes-tosterone, bioavailable testosterone, sex hor-mone binding globulin (SHBG) and aging.Conclusion: Our findings do not supportthe hypothesis that serum triglyceridelevel may be involved in the pathogenesisof prostate cancer. Furthermore, thesedata suggests that serum testosterone, bio-available testosterone and SHBG have es-sential roles in the biological pathway oftriglyceride in relation to prostate cancerdevelopment.

UP-02.095Serum Calcium as a Protective MarkerAgainst Prostate Cancer: Role ofAssociated FactorsPourmand G1, Salem S1,2, Hosseini M1,Allameh F1, Mehrsai A1

1Urology Research Center, Sina Hospital,Tehran University of Medical Sciences,Tehran, Iran, 2Dept. of Urology, CaseWestern Reserve University, Cleveland,USA

Introduction and Objectives: There areconflicting reports over the dietary intakeof calcium, circulating Vitamin D and sub-sequently serum calcium level with pros-tate carcinogenesis and yet no consistentevidence of an association between thesefactors and risk of prostate cancer (PC)has been provided, particularly in Asianpopulation with different lifestyle and di-etary habits. This study sought to furtherevaluate the possible effects of serum cal-cium level on PC risk in a different geo-graphic setting, with special regard toage, body mass index (BMI) and sex ste-roid hormones.Materials and Methods: Using data froma prospective hospital-based multi-centercase-control study, serum calcium concen-tration as well as thorough demographicand medical characteristics were deter-mined in 194 cases with newly diagnosed,clinicopathologically confirmed PC and317 controls, without any malignant dis-ease, admitted to the same network ofhospitals. Serum calcium levels were cate-gorized into tertiles. Multivariate logisticregression model was used to estimateodds ratios (OR) and corresponding 95%confidence intervals (CI) after adjustmentfor major potential confounders, includingage, BMI, smoking, alcohol, education,occupation, marital status, family historyof PC and sex hormones level.Results: The mean serum calcium level(�SD) in case and control groups was 9.22(�0.46) mg/dl and 9.48 (�0.51) mg/dl, re-spectively; this difference was proved to bestatistically significant (p � 0.001). Afteradjustment for mentioned confounders, asignificant trend of decreasing risk wasfound for serum calcium concentration (OR:0.27, 95% CI: 0.12-0.59, comparing thehighest with the lowest tertile). An increaseof 1 mg/dl in serum calcium level was asso-ciated with a significant decrease in risk ofPC (OR: 0.52; 95% CI: 0.34-0.76). Moreover,we found no correlation between the serumcalcium concentration and age, BMI, pros-tate specific antigen, total testosterone, bio-available testosterone and/or estradiol level.Conclusions: Our findings support thehypothesis that serum calcium could be

considered as a protective biomarkeragainst PC development. Furthermore,these data do not suggest sex steroid hor-mones being an intermediate in the bio-logical causal pathway between calciumconcentration and PC risk.

UP-02.096Analysis of A/G Polymorphism ofARE-I Region on PSA Gene in IranianPatients with Prostate CancerSam Zadeh M1, Hasanzad M2, Sedighi S3,Jamaldini S4, Ziaei S1

1Dept. of Urology, Shaheed LabbafinejadHospital, Shaheed Beheshti University,Tehran, Iran, 2Islamic Azad University;Tehran Medical Branch, Tehran, Iran,3St. Matthew’s UniversitySchool ofMedicine, Florida, USA, 4GeneticsResearch Center, University of SocialWelfare and Rehabilitaion Science

Introduction and Objective: Despitemuch recent progress prostate cancer isone of the most common malignancies inmen.The -158A/G polymorphism of theARE-I locus of the PSA gene (rs266882) inprostate cancer patients and benign pros-tate hyperplasia (BPH) were investigatedto determine a possible relationship ofthat locus to prostate cancer risk.Materials and Methods: Seventy-fiveprostate cancer patients and ninety-ninebenign prostate hyperplasia subjects werecompared. PSA ARE-I polymorphism analy-ses were performed using a previouslydescribed PCR-restriction fragment lengthpolymorphism (RFLP) method.Results: There were significant differencesbetween the BPH and patient groups forthe PSA-AREI genotypes; the AG and GGgenotypes show significant difference inhealthy vs. cancer patients [95% CI]. ThePSA polymorphisms may be associated withthe risk of prostate cancer development,disease progression (stage), grade of pros-tate cancer (Gleason score), total and freeblood PSA level in Iranian menConclusions: G allele carriers had a 1.65-fold higher risk (odds ratio � 1.65) of de-veloping advanced prostate cancer in ourpopulation. With further research, suchPSA-AREI polymorphism analyses mayhelp in follow up and in deciding theprognosis of prostate cancer patients.

UP-02.097Induction of Apoptosis andEnhancement of Chemosensitivity byDownregulating ofApurinic/Apyrimidinic Endonuclease

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S292 UROLOGY 78 (Supplement 3A), September 2011

1/Redox Factor-1 in Castration-resistant Prostate Cancer CellsSul C, Song K, Na Y, Lim J, Shin J,Hwang E, Oh TChungnam National University Hospital,Daejon, South Korea

Introduction and Objective: Advancedand castration-resistant prostate cancerhas long been considered as a chemo-re-sistant disease. The objectives of thisstudy are to characterize apurinic/apyrimi-dinic endonuclease 1/redox Factor-1(Ape1/Ref-1) expression levels in humanprostate cancer cell lines and evaluate theeffect of siRNA targeting the DNA repairand redox signaling protein Ape1/Ref-1.Materials and Methods: Two castrationresistant prostate cancer cell lines, Du 145and PC-3 cells were used for this study.Ape1/Ref-1 was transfected by siRNA andidentified by real time PCR, western blotand immunofluorescent staining usingconfocal laser scan microscopy. By theRT-PCR and confocal microscopy, expres-sion of Ape1/Ref-1 was detected accord-ing to concentration of docetaxel at 1, 3,5 day. Expression of Ape1/Ref-1, caspase-3according to concentration of docetaxelwas detected between Ape1/Ref-1 siRNA(�) and Ape1/Ref-1 siRNA (�) at 3 day.Cell viability according to concentrationof docetaxel was analyzed by MTT assay.Results: The expression of Ape1/Ref-1after siRNA transfection in Du 145 andPC-3 cells was 20-30%. Expression ofApe1/Ref-1 in Du 145 and PC-3 cells ac-cording to concentration of docetaxel wasincreased at 3 day. Ape1/ref-1 siRNA trans-fection chemosensitized Du 145 and PC-3cell to docetaxel and apoptotic rates inDu 145 and PC-3 cells were significantlyincreased when Ape1/Ref-1 was combinedwith docetaxel.Conclusion: The present findings indi-cate that Ape1/Ref-1 may play significantroles in the acquisition of chemo-resistantphenotype in castration resistant prostatecancer cells and targeted knockdown ofApe1/Ref-1 may enhance the effects ofcytotoxic chemotherapy in docetaxel re-sistant cells.

UP-02.098The Novel AKT-Inhibitor AZD5363Abrogates Androgen-ReceptorSignaling and Delays Hormone-Sensitive and Castration-ResistantProstate Cancer Progression in vivoThomas C1, Lamoureux F1, Crafter C2,Davies B2, Zoubeidi A1, Gleave M1

1The Vancouver Prostate Centre,University of British Columbia,

Vancouver, Canada, 2AstraZeneca,Alderley Park, Macclesfield, UK

Introduction and Objective: The PI3K/Akt pathway plays a major role in prostatecancer (PCa) progression and therefore isan attractive pharmacological target. Inthis study, we assessed the antitumoraleffects of the novel Akt-pathway inhibitor,AZD5363, in vitro and in vivo in PCa.We hypothesize that this novel drug willnot only inhibit PI3K/Akt downstreameffectors but also affect the androgen-re-ceptor (AR) signaling.Methods: LNCaP and C4-2 cells weretreated with AZD5363 and submitted towestern blot and cell viability assay.AZD5363 was tested for its ability to abro-gate AR transcriptional activity. In vivo,we used the hormone-sensitive and castra-tion-resistant (CRPC) LNCaP xenograftmodel. Mice were randomly treated withAZD5363 or control by oral gavage imme-diately (hormone-sensitive) or delayed(CRPC) after castration. Tumor volumeand serum PSA were evaluated consis-tently. Survival analysis, target gene pro-tein expression and immunohistochemis-try were evaluated for each group andmodel.Results: Here we report that AZD5363inhibits cell growth in a dose-dependentmanner in both LNCaP and C4-2 cells.Moreover, it induces cell apoptosis asmeasured with PARP cleavage expression,caspase 3 activity, and increases thesub-G1 population. Interestingly, AZD5363significantly abrogates androgen-inducedPSA transactivation and down-regulatesPSA protein expression at concentrations�1�M. These biologic events are accom-panied by inhibition of downstream PI3K/Akt signaling. Most important, targetingthe Akt-pathway with AZD5363 in vivosignificantly reduces tumor growth rate by6.4-fold in the hormone-sensitive modeland by 6.2-fold in the CRPC model com-pared to each control. Moreover, serumPSA velocity is reduced by 4.3-fold in thehormone-sensitive model and by 5.0-foldin the CRPC model compared to eachcontrol. Consistently, AZD5363 treatmentsignificantly improves biochemical- andtumor progression-free survival.Conclusions: This study reports as a pre-clinical proof-of-principle that targetingPI3K/Akt pathway with AZD5363 inhibitshormone-sensitive and castration-resistantPCa progression in vitro and in vivo, us-ing additionally the AR-axis as a pharma-codynamic tool.This work was supportedby AstraZeneca, the Deutsche For-schungsgemeinschaft (German ResearchFoundation; Grant number: TH 1482/2-

1), the Canadian Institutes of Health Re-search and l’Association pour la Recher-che sur le Cancer (France).

UP-02.099Expression of Hepatocyte GrowthFactor Activator Inhibitor Type 1(HAI-1) in Prostate CancerYasuda K, Morii A, Watanabe A,Fujiuchi Y, Komiya A, Fuse HDept. of Urology, University of Toyama,Graduate School of Medicine andPharmaceutical Sciences for Research,Toyama, Japan

Objectives: Hepatocyte growth factoractivator inhibitor type 1 (HAI-1) isKunitz-type serine protease inhibitor forhepatocyte growth factor activator andmatriptase. We have demonstrated thatserum HAI-1 levels were elevated in pa-tients with advanced-stage prostate can-cer. We investigated whether the expres-sion of HAI-1 was associated with theprogression of prostate cancer.Materials and Methods: We evaluatedthe expression of HAI-1 by immunohisto-chemistry (IHC) in 51 patients who werenegative for prostate biopsy and 75 pa-tients with prostate cancer. The relation-ship between HAI-1 expression and sev-eral clinicopathological factors and serumHAI-1 levels was analyzed. Furthermore,we evaluated expression of HAI-1 in 24castration resistance prostate cancer(CRPC) patients by IHC. Progression freesurvival was analyzed according to HAI-1expression.Results: The mean score for HAI-1 in pa-tients with negative for biopsy and pros-tate cancer patients were 1.75�0.74 and2.24�0.87, respectively. Expression ofHAI-1 in patients with prostate cancer wassignificantly higher than those with nega-tive for biopsy patients (P�0.0002). Therewere no significant differences in HAI-1expression with respect to clinical stageor tumor grade. But CRPC patients hadsignificantly lower HAI-1 expression thanpretreatment metastatic prostate cancerpatients (P�0.046). In addition, no rela-tionship was found between the HAI-1score of tumor tissues and serum HAI-1level. PSA progression free survival ratewas lower in prostate cancer patientswith negative HAI-1 expression in pre-treatment biopsy specimens than thosewith positive HAI-1 expression (P�0.031).Conclusions: It was suggested that HAI-1expression by IHC was related to tumordevelopment and androgen-independentprogression in prostate cancer. HAI-1 ex-pression was lower in biopsy specimens

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UROLOGY 78 (Supplement 3A), September 2011 S293