scholarly journals Application of 188Rhenium as an Alternative Radionuclide for Treatment of Prostate Cancer after Tumor-Specific Sodium Iodide Symporter Gene Expression

2007 ◽  
Vol 92 (11) ◽  
pp. 4451-4458 ◽  
Author(s):  
Michael J. Willhauck ◽  
Bibi-Rana Sharif Samani ◽  
Franz-Josef Gildehaus ◽  
Ingo Wolf ◽  
Reingard Senekowitsch-Schmidtke ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Therapeutic Effect ◽  
Half Life ◽  
Sodium Iodide ◽  
Specific Antigen ◽  
Volume Reduction ◽  
Sodium Iodide Symporter ◽  
Nis Gene

Abstract Context: We reported recently the induction of iodide accumulation in prostate cancer cells (LNCaP) by prostate-specific antigen promoter-directed sodium iodide symporter (NIS) expression that allowed a significant therapeutic effect of 131iodine (131I). These data demonstrated the potential of the NIS gene as a novel therapeutic gene, although in some extrathyroidal tumors, therapeutic efficacy may be limited by rapid iodide efflux due to a lack of iodide organification. Objective: In the current study, we therefore studied the potential of 188rhenium (188Re), as an alternative radionuclide, also transported by NIS, with a shorter half-life and higher energy β-particles than 131I. Results: NIS-transfected LNCaP cells (NP-1) concentrated 8% of the total applied activity of 188Re as compared with 16% of 125I, which was sufficient for a therapeutic effect in an in vitro clonogenic assay. γ-Camera imaging of NP-1 cell xenografts in nude mice revealed accumulation of 8–16% injected dose (ID)/g 188Re (biological half-life 12.9 h), which resulted in a 4.7-fold increased tumor absorbed dose (450 mGy/MBq) for 188Re as compared with 131I. After application of 55.5 MBq 131I or 188Re, smaller tumors showed a similar average volume reduction of 86%, whereas in larger tumors volume reduction was significantly increased from 73% after 131I treatment to 85% after application of 188Re. Conclusion: Although in smaller prostate cancer xenografts both radionuclides seemed to be equally effective after prostate-specific antigen promoter-mediated NIS gene delivery, a superior therapeutic effect has been demonstrated for 188Re in larger tumors.

scholarly journals Retinoic Acid-Induced Stimulation of Sodium Iodide Symporter Expression and Cytotoxicity of Radioiodine in Prostate Cancer Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (8) ◽  
pp. 3423-3432 ◽  
Author(s):  
C. Spitzweg ◽  
I. V. Scholz ◽  
E. R. Bergert ◽  
D. J. Tindall ◽  
C. Y. F. Young ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Retinoic Acid ◽  
Cancer Cells ◽  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Prostate Cancer Cells ◽  
Iodide Uptake ◽  
Killing Effect ◽  
Nis Gene

Abstract We reported recently the induction of androgen-dependent iodide uptake activity in the human prostatic adenocarcinoma cell line LNCaP using a prostate-specific antigen (PSA) promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. In the current study, we examined the regulation of PSA promoter-directed NIS expression and therapeutic effectiveness of 131I in LNCaP cells by all-trans-retinoic acid (atRA). For this purpose, NIS mRNA and protein expression levels in the NIS-transfected LNCaP cell line NP-1 were examined by Northern and Western blot analysis following incubation with atRA (10 −9 to 10−6m) in the presence of 10−9m mibolerone (mib). In addition, NIS functional activity was measured by iodide uptake assay, and in vitro cytotoxicity of 131I was examined by in vitro clonogenic assay. Following incubation with atRA, NIS mRNA levels in NP-1 cells were stimulated 3-fold in a concentration-dependent manner, whereas NIS protein levels increased 2.3-fold and iodide accumulation was stimulated 1.45-fold. This stimulatory effect of atRA, which has been shown to be retinoic acid receptor mediated, was completely blocked by the pure androgen receptor antagonist casodex (10−6m), indicating that it is androgen receptor dependent. The selective killing effect of 131I in NP-1 cells was 50% in NP-1 cells incubated with 10−9m mib. This was increased to 90% in NP-1 cells treated with atRA (10−7m) plus 10−9m mib. In conclusion, treatment with atRA increases NIS expression levels and selective killing effect of 131I in prostate cancer cells stably expressing NIS under the control of the PSA promoter. Therefore atRA may be used to enhance the therapeutic response to radioiodine in prostate cancer cells following PSA promoter-directed NIS gene delivery.

Prostate-specific antigen (PSA) protein does not affect growth of prostate cancer cells in vitro or prostate cancer xenografts in vivo

The Prostate ◽  
2003 ◽  
Vol 56 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Samuel R. Denmeade ◽  
Ivan Litvinov ◽  
Lori J. Sokoll ◽  
Hans Lilja ◽  
John T. Isaacs
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Prostate Cancer Cells

scholarly journals CR6-Interacting Factor 1 Represses the Transactivation of Androgen Receptor by Direct Interaction

2008 ◽  
Vol 22 (1) ◽  
pp. 33-46 ◽  
Author(s):  
Ji Ho Suh ◽  
Minho Shong ◽  
Hueng-Sik Choi ◽  
Keesook Lee
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Prostate Specific Antigen ◽  
Transcriptional Activation ◽  
Mrna Level ◽  
Specific Antigen ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Target Promoters

Abstract CR6-interacting factor 1 (CRIF1) was previously identified as a nuclear protein that interacts with members of the Gadd45 family and plays a role as a negative regulator in cell growth. However, the nuclear function of CRIF1 remains largely unknown. In this study, we demonstrate that CRIF1 acts as a novel corepressor of the androgen receptor (AR) in prostatic cells. Transient transfection studies show that CRIF1 specifically represses AR transcriptional activation of target promoters in a dose-dependent manner. Additionally, CRIF1 is recruited with AR to the endogenous AR target promoters. In vivo and in vitro protein interaction assays reveal that CRIF1 directly interacts with AR via the activation function-1 domain of AR. Interestingly, both the N-terminal and C-terminal half-regions of CRIF1 are independently capable of interacting with and repressing the transactivation of AR. CRIF1 represses AR transactivation through competition with AR coactivators. In addition, the CRIF1-mediated inhibition of AR transactivation involves the recruitment of histone deacetylase 4. Down-regulation of CRIF1 by small interfering RNA increases the transactivation of AR and the mRNA level of the AR target gene prostate-specific antigen, whereas the overexpression of CRIF1 decreases the prostate-specific antigen mRNA level. Finally, the overexpression of CRIF1 inhibits the androgen-induced proliferation and cell cycle progression of prostate cancer cells. Taken together, these results suggest that CRIF1 acts as an AR corepressor and may play an important role in the regulation of AR-positive growth of prostate cancer.

scholarly journals Measurement of the Complex between Prostate-specific Antigen and α1-Protease Inhibitor in Serum

1999 ◽  
Vol 45 (6) ◽  
pp. 814-821 ◽  
Author(s):  
Wan-Ming Zhang ◽  
Patrik Finne ◽  
Jari Leinonen ◽  
Satu Vesalainen ◽  
Stig Nordling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protease Inhibitor ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Serum Samples ◽  
Free Psa ◽  
Total Psa ◽  
Healthy Females

Abstract Background: Prostate-specific antigen (PSA) occurs in serum both free and in complex with protease inhibitors. The complex with α1-antichymotrypsin (ACT) is the major form in serum, and the proportion of PSA-ACT is higher in prostate cancer (PCa) than in benign prostatic hyperplasia (BPH). PSA also forms a complex with α1-protease inhibitor (API) in vitro, and the PSA-ACT complex has been detected in serum from patients with prostate cancer. The aim of the present study was to develop a quantitative method for the determination of PSA-API and to determine the serum concentrations in patients with PCa and BPH. Methods: The assay for PSA-API utilizes a monoclonal antibody to PSA as capture and a polyclonal antibody to API labeled with a Eu-chelate as a tracer. For calibrators, PSA-API formed in vitro was used. Serum samples were obtained before treatment from 82 patients with PCa, from 66 patients with BPH, and from 22 healthy females. Results: The concentrations of PSA-API are proportional to the concentrations of total PSA. PSA-API comprises 1.0–7.9% (median, 2.4%) of total immunoreactive PSA in PCa and 1.3–12.2% (median, 3.6%) in BPH patients with serum PSA concentrations >4 μg/L. In patients with 4–20 μg/L total PSA, the proportion of PSA-API serum is significantly higher in BPH (median, 4.1%) than in PCa (median, 3.2%; P = 0.02). Conclusions: The proportion of PSA-API in serum is lower in patients with PCa than in those with BPH. These results suggest that PSA-API is a potential adjunct to total and free PSA in the diagnosis of prostate cancer.

scholarly journals Taking Advantage of the TGFB1 Biology in Differentiated Thyroid Cancer to Stimulate Sodium Iodide Symporter (NIS)-Mediated Iodide Uptake in Engineered Mesenchymal Stem Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1033-A1033
Author(s):  
Yang Han ◽  
Viktoria F Koehler ◽  
Nathalie Schwenk ◽  
Kathrin A Schmohl ◽  
Rebekka Spellerberg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Nis Gene

Abstract The sodium iodide symporter (NIS) mediates the active transport of iodide into thyroid follicular cells, providing the basis for the use of radioiodide for diagnostic imaging and therapy of differentiated thyroid cancer and also non-thyroidal tumors after tumor-selective NIS gene transfer. Based on their excellent tumor-homing capacity, mesenchymal stem cells (MSCs) can be employed as tumor-selective NIS gene delivery vehicles. Transgenic expression of NIS in genetically engineered MSCs allows noninvasive imaging of functional NIS expression as well as therapeutic application of 131I. The use of promoters activated by tumor micromilieu-derived signals to drive NIS expression enhances selectivity and effectiveness, while limiting potential off-target effects. In this study we aimed to exploit the central role of transforming growth factor B1 (TGFB1) in tumor milieu-associated signaling using a TGFB1-inducible synthetic SMAD-responsive promoter to selectively drive NIS-transgene expression in engineered MSCs (SMAD-NIS-MSC) in the context of differentiated thyroid cancer based on the critical role of TGFB1 in the pathogenesis of radioiodine refractory differentiated thyroid cancer. To evaluate the TGFB1 expression in thyroid cancer cell lines, the TGFB1 concentration in conditioned medium (CM) from an array of established human papillary thyroid cancer (PTC) cell lines (BCPAP and K1) was measured by ELISA. BCPAP-CM showed a higher concentration of TGFB1, while a lower concentration was measured in K1-CM. Stimulation of SMAD-NIS-MSCs with PTC-CM showed a significant increase of NIS-mediated radioiodide-125 uptake in these MSCs in vitro. In addition, iodide uptake in SMAD-NIS-MSCs was significantly stimulated by co-culture with thyroid cancer cells. Cell migration assay was performed to validate the effect of PTC-CM in MSC recruitment. MSCs subjected to a gradient between tumor CM and serum free medium showed a directed chemotaxis towards CM with increased forward migration index (FMI) and center of mass (CoM). In a next step, based on the in vitro studies, SMAD-NIS-MSCs will be systemically applied via the tail vein to mice harboring subcutaneous PTC tumors and tumoral iodide uptake will be monitored by 123I-scintigraphy. Taken together, these data indicate the feasibility of commandeering TGF-β/SMAD signaling in the TGFB1-rich tumor environments of radioiodine refractory differentiated thyroid carcinomas to re-establish functional NIS expression using engineered mesenchymal stem cells as therapy vehicles.

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