ABSTRACT
Urotensin II (UT-II) is a potent vasoconstrictor peptide and its receptor (UTR) was correlated with human cortico-adrenal carcinoma proliferation. In this study, we have evaluated the correlation between UTR expression and prognosis of human prostate adenocarcinoma and the involvement of this receptor in the regulation of biological properties on both in vivo and in vitro models. UTR mRNA and protein, evaluated by real-time PCR and Western blotting, respectively, were expressed at high levels only in androgen-dependent LNCaP cells. In order to investigate UTR changes occurring in human prostate tumorigenesis, we have also evaluated the expression of UTR in vivo in 195 human prostate tissue samples. UTR was always expressed at low intensity in hyperplastic tissues and at high intensity in well-differentiated carcinomas (Gleason 2-3). Moreover, we have evaluated the effects of an antagonist of UTR, urantide on migration and invasion of LNCaP cells. Urantide induced a dose-dependent decrease of motility and invasion of LNCaP cells whose characteristic ameboid movement seems to be advantageous for their malignancy. These effects were paralleled by down-regulating the autophosphorylation of focal adhesion kinase and the integrin surface expression on LNCaP cells. The effects on cell motility and invasion were likely due to the inhibition of RhoA activity induced by both urantide and shRNA UTR. These data suggest that UTR can be considered a prognostic marker in human prostate adenocarcinoma patients.
Subject(s)
Adenocarcinoma/diagnosis , Biomarkers, Tumor/metabolism , Cell Movement , Prostatic Neoplasms/diagnosis , Receptors, G-Protein-Coupled/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , Humans , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , RNA, Messenger/metabolism , Receptors, G-Protein-Coupled/genetics , Treatment Outcome , Tumor Cells, CulturedABSTRACT
BACKGROUND: Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid AN d TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC. RESULTS: The maximum tolerated dose was not achieved with sequence A. Two patients at third level of sequence B developed dose limiting toxicity. A disease control was obtained in six out of nine patients treated with sequence A, where a decrease of biological markers and PSA were also observed. No evidence of anti-tumor activity was observed in patients treated with sequence B. PATIENTS AND METHODS: Twenty-two patients enrolled into the study (median age: 73 years; range: 43-80) received one of three escalated doses of DTX (30, 40 and 50 mg/m(2)) in combination with a fixed dose of ZOL (2 mg), both administered every 14 days in two different sequences: DTX at the day 1 followed by ZOL at the day 2 (sequence A) or the reverse (sequence B). Patients were evaluated for adverse events and serum IL-8, MMP-2 and MMP-9 were evaluated prior and after therapy with the two sequences of administration of DTX and ZOL. CONCLUSIONS: The bi-weekly combination of DTX (50 mg/m(2)) followed by ZOL was feasible and show promising anti-tumor activity.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Anemia/chemically induced , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Diphosphonates/administration & dosage , Diphosphonates/adverse effects , Docetaxel , Dose-Response Relationship, Drug , Drug Administration Schedule , Feasibility Studies , Fever/chemically induced , Humans , Imidazoles/administration & dosage , Imidazoles/adverse effects , Infusions, Intravenous , Interleukin-8/blood , Male , Matrix Metalloproteinase 2/blood , Matrix Metalloproteinase 9/blood , Middle Aged , Neutropenia/chemically induced , Orchiectomy , Prostate-Specific Antigen/blood , Prostatic Neoplasms/surgery , Taxoids/administration & dosage , Taxoids/adverse effects , Treatment Outcome , Zoledronic AcidABSTRACT
Metastatic renal cell carcinoma (RCC) is notoriously chemoresistant; up until recently, immunotherapy (in particular interferon-alpha) has represented the treatment of choice. The understanding of the biology of RCC has resulted in the development of targeted therapies. In particular, multikinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib), antivascular endothelial growth factor agents (bevacizumab), and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) now have a role in the approach to different subsets of RCC. Sunitinib is indicated for the first-line therapy of metastatic RCC as a consequence of a positive phase III trial versus interferon-alpha; sorafenib is now registered for the second-line treatment of RCC, which was earlier treated with cytokine as a consequence of a positive phase III trial versus placebo. Bevacizumab is also indicated in the first-line treatment of metastatic RCC given in combination with interferon-alpha as a consequence of two positive phase III trials. Temsirolimus, unlike the other agents, has also shown activity in poor-prognosis patients, and is now the treatment of choice in previously untreated poor-prognosis RCC as a single agent. Everolimus can be considered as the best therapeutic option in patients with RCC pretreated with targeted agents as a consequence of a positive phase III study versus best supportive care. Markers for appropriate treatment selection, combined use of targeted agents, treatment of special histologies, and adjuvant and neoadjuvant setting represent important special issues to be dealt with in future studies.
