Author:
Palma Rocchi, Eliana Beraldi, Susan Ettinger, Ladan Fazli, Robert L Vessella, Colleen Nelson, Martin Gleave
Publication Date:
01 Dec 2005
Description:
One strategy to improve therapies in prostate cancer involves targeting cytoprotective genes activated by androgen withdrawal to delay the emergence of the androgen-independent (AI) phenotype. The objectives of this study were to define changes in Hsp27 levels after androgen ablation and to evaluate the functional relevance of these changes in AI progression. Using a tissue microarray of 232 specimens of hormone-naïve and post-hormone ablation–treated prostate cancer, we found that Hsp27 levels increase after androgen ablation to become highly expressed (>4-fold, P ≤ 0.01) in AI tumors. Hsp27 overexpression rendered LNCaP cells highly resistant to androgen withdrawal both in vitro and in vivo. Tumor volume and serum prostate–specific antigen levels increased 4.3- and 10-fold faster after castration when Hsp27 was overexpressed. Treatment of LNCaP tumor cells in vitro with Hsp27 …
Author:
Kazuki Yamanaka, Palma Rocchi, Hideaki Miyake, Ladan Fazli, Bob Vessella, Uwe Zangemeister-Wittke, Martin E Gleave
Publication Date:
01 Nov 2005
Source:
Molecular cancer therapeutics
Description:
Bcl-2 and Bcl-xL are associated with treatment resistance and progression in many cancers, including prostate cancer. The objective of this study was to determine whether a novel bispecific antisense oligonucleotide targeting both Bcl-2 and Bcl-xL induces apoptosis and enhances chemosensitivity in androgen-independent PC3 prostate cancer cells. An antisense oligonucleotide with complete sequence identity to Bcl-2 and three-base mismatches to Bcl-xL selected from five antisense oligonucleotides targeting various regions with high homology between Bcl-2 and Bcl-xL was found to be the most potent inhibitor of both Bcl-2 and Bcl-xL expression in PC3 cells. This selected Bcl-2/Bcl-xL bispecific antisense oligonucleotide reduced mRNA and protein levels in a dose-dependent manner, reducing Bcl-2 and Bcl-xL protein levels to 12% and 19%, respectively. Interestingly, Mcl-1 was down-regulated as well …
Author:
Kazuki Yamanaka, Palma Rocchi, Hideaki Miyake, Ladan Fazli, Bob Vessella, Uwe Zangemeister-Wittke, Martin E Gleave
Publication Date:
01 Nov 2005
Source:
Molecular cancer therapeutics
Description:
Bcl-2 and Bcl-xL are associated with treatment resistance and progression in many cancers, including prostate cancer. The objective of this study was to determine whether a novel bispecific antisense oligonucleotide targeting both Bcl-2 and Bcl-xL induces apoptosis and enhances chemosensitivity in androgen-independent PC3 prostate cancer cells. An antisense oligonucleotide with complete sequence identity to Bcl-2 and three-base mismatches to Bcl-xL selected from five antisense oligonucleotides targeting various regions with high homology between Bcl-2 and Bcl-xL was found to be the most potent inhibitor of both Bcl-2 and Bcl-xL expression in PC3 cells. This selected Bcl-2/Bcl-xL bispecific antisense oligonucleotide reduced mRNA and protein levels in a dose-dependent manner, reducing Bcl-2 and Bcl-xL protein levels to 12% and 19%, respectively. Interestingly, Mcl-1 was down-regulated as well …
Author:
Alan So, Palma Rocchi, Martin Gleave
Publication Date:
01 Sep 2005
Source:
Current opinion in urology
Description:
Recent developments of the in-vitro and animal in-vivo effectiveness of antisense treatment in bladder cancer provide the foundation to pursue future phase I clinical trials. Antisense oligonucleotide technology is a promising tool that may become an effective method of treating bladder cancer.
Author:
F Fina, X Muracciole, P Rocchi, I Nanni-Metellus, C Delfino, L Daniel, C Dussert, L’H Ouafik, PM Martin
Publication Date:
01 Sep 2005
Source:
The Journal of Steroid Biochemistry and Molecular Biology
Description:
After castration or therapeutic hormone deprivation, most cancer of the prostate (CaP) cells develop androgen-independent (AI) growth. In this work, we studied the effect of androgen depletion (castration) on the growth of experimental model LuCaP 23.1 xenograft. A total of 101 nude mice were implanted and analysed for their growth profile before experimental period 1 (11 weeks) and after castration experimental period 2 (15 weeks). For specific periods, tumors were harvested and assessed for molecular marker expression specific for CaP. Taking into account tumor dynamic growth, prior to castration we found 37 fast growing (FG) tumors (948.9±76.9mm3) and 63 slow growing (SG) tumors (229.6±18.4mm3). Real-time quantitative RT-PCR showed that in comparison to SGs, FGs contained elevated expression of epidermal growth factor receptor type 1 (HER1), urokinase plasminogen activator (uPA), thymidine …
Author:
David Taïeb, Cédric Malicet, Stéphane Garcia, Palma Rocchi, Christiane Arnaud, Jean-Charles Dagorn, Juan L Iovanna, Sophie Vasseur
Publication Date:
01 Jul 2005
Description:
The p8 protein is a transcription factor that regulates the expression of genes involved in cell defense against the adverse effects of stress. Its expression is strongly, rapidly, and transiently induced in most cells on exposure to various stress agents. This study assessed the role of p8 in the response of the liver to CCl 4-induced injury. We found that p8 was indeed overexpressed in the liver after CCl 4 administration. Hepatic injury following CCl 4 injection was monitored in wild-type and p8−/− mice. Serum alanine and aspartate aminotransferase activities were higher and peaked earlier in p8−/− mice than in wild-type mice, which is in agreement with the observation of significantly larger areas of necrosis in p8−/− liver. Absence of p8 expression is therefore associated with increased liver sensitivity to CCl 4. In fact, CCl 4 toxicity is mediated by derivatives generated by its conversion by the enzyme CYP2E1. It is …
Author:
Palma Rocchi, Eliana Beraldi, Susan Ettinger, Martin E Gleave
Publication Date:
01 Apr 2005
Source:
The Journal of Urology
Description:
METHODS: Between January 1991 and September 2004, 14 patients with invasive carcinoma of the urethra were managed with a modified Nigro chemoradiation protocol. Thirteen patients had squamous cell carcinoma and one had adenocarcinoma of the urethra. The pendulous urethra was the origin in 5 patients and in 9 patients the bulbo-membranous urethra was the primary site of cancer. Presenting symptoms in patients included a history of urethral strictures in 8, painful mass in I, penile ulceration in 2, lower urinary tract symptoms (dysuria) and pain in 3. Initial evaluation included retrograde urethrogram, cystourethroscopy with urethral biopsy and CT scan of the chest and abdomen. Clinical stage was T2NO in I, T2N2 in I, T3NO in 6, T3Nl in I, T3N2 in I, and T4NO in 4. The initial treatment was by suprapubic cystotomy urinary diversion. The modified chemo-radiation regimen consisted of 45 Gy in 25 …
Author:
Palma Rocchi, Xavier Muracciole, Frederic Fina, Dave J Mulholland, Gilles Karsenty, Jacqueline Palmari, L'Haucine Ouafik, Franck Bladou, Pierre-Marie Martin
Publication Date:
01 Dec 2004
Description:
After therapeutic hormone deprivation, most prostate cancer (PrCa) cells develop androgen-independent (AI) growth. PrCa is highly heterogeneous and multifocal, suggesting that several molecular processes or pathways may be contributing to AI. The human LuCaP 23.1 xenograft model retains clinical hallmarks of PrCa, including heterogeneous growth, PSA production, androgen-responsiveness and progression to AI. In this work, we studied the effect of androgen depletion (castration) on the growth of LuCaP 23.1 xenografts. A total of 100 nude mice were implanted and analysed for their growth profiles before and after castration. By 11 and 15 weeks, tumours were harvested and assessed for molecular marker expression specific for PrCa. Prior to castration we found 37 fast growing (FG) tumours (948.9±76.9 mm 3) and 63 slow growing (SG) tumours (229.6±18.4 mm 3), a previously undescribed result for this …
Author:
Palma Rocchi, Alan So, Satoko Kojima, Maxim Signaevsky, Eliana Beraldi, Ladan Fazli, Antonio Hurtado-Coll, Kazuki Yamanaka, Martin Gleave
Publication Date:
15 Sep 2004
Description:
Heat shock protein 27 (Hsp27) is a chaperone implicated as an independent predictor of clinical outcome in prostate cancer. Our aim was to characterize changes in Hsp27 after androgen withdrawal and during androgen-independent progression in prostate xenografts and human prostate cancer to assess the functional significance of these changes using antisense inhibition of Hsp27. A tissue microarray was used to measure changes in Hsp27 protein expression in 232 specimens from hormone naive and posthormone-treated cancers. Hsp27 expression was low or absent in untreated human prostate cancers but increased beginning 4 weeks after androgen-ablation to become uniformly highly expressed in androgen-independent tumors. Androgen-independent human prostate cancer PC-3 cells express higher levels of Hsp27 mRNA in vitro and in vivo, compared with androgen-sensitive LNCaP cells …
Author:
Palma Rocchi, Satoko Kojima, Eliana Beraldi, Ladan Fazli, Martin E Gleave
Publication Date:
01 Apr 2004
Source:
The Journal of Urology
Description:
METHODS Expression of BMPs and the BMP antagonists Noggin and SOST were analysed by RT-PCR and real time quantitative PCR. RESULTS The osteolytic, highly tumorigenic and metastatic human PCa cell lines PC3, its variant PC3M-Pro4, and the BCa cell line MDA-MB-231, constitutively express BMP-2,-3 and-4, and Noggin mRNAs. The PCa cell lines LNCaP and its osteoblastic and metastatic variants C4-2 and C4-2B4, as well as the osteoblastic BCa cell lines T-470 and ZR-75-1 do not express BMP-2,-3 and-4 mRNAs but BMP-6. SOST mRNA is expressed at a low level exclusively in osteolytic MDA-MB-231 cells. Neither stimulation with TGF-{31 nor BMP-2 induces SOST or Noggin expression in these cell lines. CONCLUSIONS Our data support the hypothesis that expression of BMPs may contribute to local or metastatic progression of PCa and BCa cell lines. Loss of either or both BMP-antagonists …
