ABSTRACT
PURPOSE: Control of metastatic prostate cancer (CaP) is an elusive objective. Some 30% of patients with clinically localized CaP will develop micrometastatic disease. Defining the expression of tumor-associated antigens on CaP will enable appropriate selection of therapeutic targets. METHODS AND MATERIALS: The expression of tumor-associated antigens on CaP cell lines (PC-3, DU 145, and LNCaP-LN3) was detected by immunohistochemistry and flow cytometry. Test and control alpha-conjugates were prepared using monoclonal antibodies, an inhibitor, plasminogen activator inhibitor type 2, that binds to the cell-membrane-bound protease, urokinase plasminogen activator, and a control protein labeled with (213)Bi using standard methods. These were used singly or together against three different CaP cell lines in vitro. The cytotoxicity of the alpha-conjugates was assessed using the [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] (MTS) assay. RESULTS: The PC-3 and DU 145 cancer cell lines expressed antigens that bind monoclonal antibodies BLCA-38 and #394 (mouse anti-human urokinase plasminogen activator B-chain) but not J591. The LNCaP-LN3 cells bound J591 but not #394 or BLCA-38. For the PC-3, DU 145, and LNCaP-LN3 cell lines, multiple-targeted alpha-therapy combining four alpha-conjugates (one-quarter doses of each) gave D(0) (37% cell survival) values of 15, 17, and 27 microCi/mL compared with those of the controls of 272, 289, and 281 microCi/mL, respectively. CONCLUSION: Metastatic prostate cancer-associated antigens recognized by multiple monoclonal antibodies are potential targets for alpha-therapy. Multiple-targeted alpha-therapy produced cytotoxicity specific to three CaP cell lines and may form the basis of treatment for micrometastatic CaP, overcoming the heterogeneity of expression of the targeted antigens.
Subject(s)
Antigens, Neoplasm/analysis , Bismuth/therapeutic use , Prostatic Neoplasms/immunology , Prostatic Neoplasms/radiotherapy , Radioimmunotherapy/methods , Radioisotopes/therapeutic use , Antibodies, Monoclonal/therapeutic use , Apoptosis , Cell Line, Tumor/immunology , Cell Proliferation/radiation effects , Humans , Immunoconjugates/therapeutic use , Male , Plasminogen Activator Inhibitor 2/therapeutic use , Prostatic Neoplasms/pathologySubject(s)
Adenocarcinoma/secondary , Bone Neoplasms/secondary , Disease Models, Animal , Prostatic Neoplasms/pathology , Animals , Humans , Infusions, Parenteral , Male , Mice , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Neoplasm Transplantation , Transplantation, Heterologous , Tumor Cells, CulturedSubject(s)
Prostatic Neoplasms/pathology , Tissue Fixation/methods , Biomarkers, Tumor/analysis , DNA/isolation & purification , Fixatives/pharmacology , Humans , Immunoenzyme Techniques , Male , Prostatic Neoplasms/chemistry , Prostatic Neoplasms/genetics , RNA/isolation & purification , Tissue Preservation/methodsABSTRACT
Participants took part in two speech tests. In both tests, a model speaker produced vowel-consonant-vowels (VCVs) in which the initial vowel varied unpredictably in duration. In the simple response task, participants shadowed the initial vowel; when the model shifted to production of any of three CVs (/pa/, /ta/ or /ka/), participants produced a CV that they were assigned to say (one of /pa/, /ta/ or /ka/). In the choice task, participants shadowed the initial vowel; when the model shifted to a CV, participants shadowed that too. We found that, measured from the model's onset of closure for the consonant to the participant's closure onset, response times in the choice task exceeded those in the simple task by just 26 ms. This is much shorter than the canonical difference between simple and choice latencies [100-150 ms according to Luce (1986)] and is near the fastest simple times that Luce reports. The findings imply rapid access to articulatory speech information in the choice task. A second experiment found much longer choice times when the perception-production link for speech could not be exploited. A third experiment and an acoustic analysis verified that our measurement from closure in Experiment 1 provided a valid marker of speakers' onsets of consonant production. A final experiment showed that shadowing responses are imitations of the model's speech. We interpret the findings as evidence that listeners rapidly extract information about speakers' articulatory gestures.
ABSTRACT
BACKGROUND: To improve the therapy of advanced prostate cancer (CaP), it is critical to develop animal models that mimic CaP bone metastases. Unlike the human disease, CaP xenograft models rarely metastasize spontaneously to bone from the orthotopic site of primary tumor growth. METHODS: Single-cell suspensions of LNCaP, PC-3, LuCaP 35, and LuCaP 23.1 CaP cells were injected directly into tibia of SCID mice. Immunohistochemistry and bone histomorphometrical analyses were performed to characterize these osseous-CaP models. RESULTS: LuCaP 23.1 yields an osteoblastic response, LNCaP yields mixed lesions, and LuCaP 35 and PC-3 result in osteolytic responses. We have detected osteoprotegerin, RANK ligand, parathyroid hormone-related protein, and endothelin-1, proteins associated with bone growth and remodeling, in the CaP cells grown in the bone. CONCLUSIONS: These animal models can be used to study biological interactions, pathways, and potential therapeutic targets, and also to evaluate new agents for treatment and prevention of CaP bone metastasis.
