INHIBITION OF HUMAN PROSTATE CANCER PROGRESSION BY ADMINISTRATION OF GREEN TEA CATECHINS: A TWO YEARS LATER FOLLOW-UP UPDATE

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THE JOURNAL OF UROLOGY®

,QWKLVVWXG\ZHK\SRWKHVL]HWKDWRUDOFRQVXPSWLRQRIWKHVHÀDYRQRLGV reduces the incidence and progression of prostate cancer in a transgenic animal model. METHODS: We employed the Transgenic Adenocarcinoma of the Murine Prostate (TRAMP) model. Mice (20 per group) were fed one of 4 diets ad libitum for 28 weeks from weaning: 1) Flavonoid free control,  ¿VHWLQ '+&DQG FRPELQDWLRQÀDYRQRLGGLHW0LFH underwent weekly body weight measurements and were monitored for VLJQVRIWR[LFLW\$WZHHNVRIDJHPLFHZHUHHXWKDQL]HGDQGVHUXP and tissue collected for further analysis. RESULTS: There was a 63% reduction in wet prostate tumor ZHLJKWLQWKHFRPELQDWLRQÀDYRQRLGJURXSFRPSDUHGWRFRQWUROPHDQ 2.2g vs 5.8g, p=0.0033). In addition, we observed a 44% reduction in the number of mice with histologic evidence of prostate cancer in the FRPELQDWLRQ ÀDYRQRLG JURXS FRPSDUHG WR WKH ÀDYRQRLGIUHH FRQWURO YVS  ZLWKQRQVLJQL¿FDQWUHGXFWLRQVQRWHGIRUWKH ¿VHWLQDQG'+&DORQHJURXSV7KHUHZDVQRHYLGHQFHRIWR[LFLW\EDVHG on body weight measurements, histological examination of major organs DQG KHPDWRORJLFDO SDUDPHWHUV$QDO\VLV RI ÀDYRQRLG OHYHOV E\ OLTXLG FKURPDWRJUDSK\PDVV VSHFWURPHWU\ FRQ¿UPHG WDUJHW VLWH DYDLODELOLW\ RIXQDOWHUHGÀDYRQRLGLQSURVWDWHWLVVXH &21&/86,216$ FRPELQDWLRQ ÀDYRQRLG GLHW LV VKRZQ WR inhibit the progression of prostate carcinogenesis in a transgenic model. This study lays the foundation for future chemoprevention studies HPSOR\LQJWKHVHÀDYRQRLGVLQKXPDQV Source of Funding: Canadian Prostate Cancer Research Initiative.

637 FUNCTIONAL PEPTIDE THERAPY WITH PTEN IN PROSTATE CANCER Motoyoshi Tanaka, Satoshi Anai*, Keigo Saito, Marco De Velasco, Atsushi Tomioka, Kazuhiro Yoshikawa, Hirotsugu Uemura. Osaka Sayama, Japan, Kashihara, Japan, and Nagakute, Japan. INTRODUCTION AND OBJECTIVE: We have demonstrated that the conditional gene targeting of Pten, aiming to cause mouse prostate specific deletion of Pten, develops sequentially prostate carcinoma through atypia and prostatic intraepithelial neoplasia (PIN). In WKLVVWXG\ZHKDYHGHVLJQHGDQGV\QWKHVL]HG3WHQIXQFWLRQDOSHSWLGHV and test whether treatment with these functional peptides can be a potential for cancer therapy. METHODS: Pten protein forms 403 amino acids (AA) and encodes a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and contains a tensin like domain as well as a catalytic domain similar to that RIWKHGXDOVSHFL¿FLW\SURWHLQW\URVLQHSKRVSKDWDVHVZKLFKQHJDWLYHO\ regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. We designed 2 kinds of minimum functional peptides from Pten phosphatase domain, which represent Pten-84 (19 $$ DQG3WHQ$$ 7RWHVWWKHHI¿FDF\RIWKHVHSHSWLGHVLQ3&D cells, Pten peptides were conjugated with Wr-T transporter peptide (Pten/ Wr-T) to augment intracellular delivery of treatment peptides. 5(68/767UHDWPHQW ZLWK 3WHQ:U7 VKRZHG D VLJQL¿FDQW growth inhibition in PC-3 (PTEN deletion), DU-145 (PTEN wild-type), and LNCaP (PTEN deletion) prostate cancer cell lines, represented by 16.7%, 40%, and 72.4% 3 days after treatment, respectively. We also FRQ¿UPHGSUHFLVHDQGVXFFHVVIXOLQFRUSRUDWLRQRI3WHQ:U7FRQMXJDWH ODEHOHGZLWK),7&LQWRFDQFHUFHOOVHYHQDIWHUKUVE\ÀXRUHVFHQW microscopy. In cell cycle analysis, Pten/Wr-T potentiated G1 cell cycle accumulation or arrest in all of PCa cell lines. Furthermore, treatment with Pten/Wr-T resulted in down-regulation of phosphorylated Akt expression in PC-3 and LNCaP cells by western blot analysis. Based on our in vitro data, we applied direct injection of Pten/Wr-T conjugate into the nude mouse subcutaneous PC-3 tumor model. In vivo treatment with Pten/ :U7VLJQL¿FDQWO\VXSSUHVVHGWXPRUJURZWKFRPSDUHGWRWKRVHWUHDWHG with Wr-T peptide alone over 30 days. In the tumor tissues treated with Pten/Wr-T, enhanced apoptosis (TUNEL), inhibited cellular proliferation (PCNA), and down-regulated phosphorylated Akt expression were observed.

Vol. 179, No. 4, Supplement, Monday, May 19, 2008

&21&/86,2167KHVH¿QGLQJVGHPRQVWUDWHWKDWSHSWLGH related molecular targeting therapy using Pten/Wr-T can be a promising clinical application for the treatment of PCa. Source of Funding: Ministry of Education, Sports, Science and Technology of Japan, Grant-in-Aid19591876 (M. Tanaka).

638 INHIBITION OF HUMAN PROSTATE CANCER PROGRESSION BY ADMINISTRATION OF GREEN TEA CATECHINS: A TWO YEARS LATER FOLLOW-UP UPDATE Brausi Maurizio*, Bettuzzi Saverio, Peracchia Giancarlo, Rizzi Federica, Corti Arnaldo. Modena, Italy, and Parma, Italy. INTRODUCTION AND OBJECTIVE: Prostate cancer is an ideal target for chemoprevention strategies that, at present, may be WKHEHVWDSSURDFKWR¿JKWLW$JURZLQJERG\RIHYLGHQFHKDVVXJJHVWHG that biologically active compounds from green tea (catechins: the most common are EGCG, EGC, ECG and EC) might posses anti-tumour activity. Recently we showed that a Green Tea Catechins extract (GTCs) was very effective at inhibiting cancer growth in vitro and in animal model , triggering apoptotic death in cancer cells probably through induction of the nuclear form of Clusterin. In 2006 we published the result of a clinical trial demonstrating that about 90% inhibition of CaP development was indeed achievable by oral administration of GTCs to humans for \HDU$OWKRXJKWKLVLVWKH¿UVWVWXG\VKRZLQJWKDW*7&VDUHVDIHDQG very effective for treating pre-malignant lesions , it is evident that this LPSRUWDQWUHVXOWQHHGVDFRQ¿UPDWLRQZLWKDODUJHUVWXG\%XWDQRWKHU important issue is still open: understanding whether CaP onset was GH¿QLWLYHO\SUHYHQWHGRUVLPSO\GHOD\HGE\WUHDWPHQW7KHDLPRIWKLV study was to evaluate results the after 2 years. METHODS: In the 2006 study, a cohort of 60 human volunteers bearing HG-PIN, the main pre-malignant lesion of CaP, were given 600mg/die of GTCs (n = 30) or placebo (n = 30) for 1y. At the end of the study, only 1 tumour was diagnosed among the GTCs-treated men, while 9 cancers were found among the placebo-treated men, with no VLJQL¿FDQWVLGHRUDGYHUVHHIIHFWVUHFRUGHG7RFKHFNZKHWKHU&D3RQVHW ZDVGH¿QLWLYHO\SUHYHQWHGRUVLPSO\GHOD\HGE\WUHDWPHQWZHPDQDJHG to convince about 50% of patients from both arms (all asymptomatic) to undergo another round of prostate mapping by needle biopsy 2ys after suspension of GTCs administration. RESULTS: We detected 1 more cancer in the cohort previously belonging to the GTCs-arm, and 2 more in that once belonging to the placebo-arm. Thus, 3ys after the beginning of the study and 2 ys DIWHUVXVSHQVLRQRI*7&VDGPLQLVWUDWLRQ¿QDOUHVXOWVZHUHFDQFHU in untreated volunteers versus 2 in those given GTCs for 1y. CONCLUSIONS: This novel data further strengthen our previous result, strongly suggesting that CaP development might be GH¿QLWLYHO\LQKLELWHGLQPDQEHDULQJ+*3,1E\DGPLQLVWUDWLRQRIPJ die of GTCs for just 1y. Source of Funding:0DXUL]LR%UDXVL

639 RAMAN MOLECULAR IMAGING OF PROSTATE CANCER: CAN RAMAN SPECTROSCOPY BE USED TO PREDICT PATIENT OUTCOME AFTER RADICAL PROSTATECTOMY? Matthew K Tollefson*, James S Magera, Thomas Sebo, Jeffrey Cohen, Amy Drauch, John Maier, Igor Frank. Rochester, MN, and Pittsburgh, PA. INTRODUCTION AND OBJECTIVE: Raman molecular imaging (RMI) combines digital imaging and analytical spectroscopy to produce images where each pixel contains a Raman spectrum. RMI has the potential to supplement current histopathological evaluation of prostate cancer to provide more information about potential disease course. In this study, RMI was evaluated as a tool to predict disease outcome in patients diagnosed with Gleason Score 7 prostate cancer. Our objective was to determine if Raman imaging can differentiate between Gleason 7 cases that progress to metastatic disease and those that do not. 0(7+2'6:HLGHQWL¿HGSDWLHQWVWKDWXQGHUZHQWUDGLFDO retropubic prostatectomy for Gleason 7 adenocarcinoma of the prostate. Half progressed to metastatic disease and half had no evidence of