Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007112 (prostatic adenocarcinoma)
 2,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Currently, no curative therapy for metastatic prostate cancer exists. Causing prostate cancer cells to express functionally active sodium iodide symporter (NIS) would enable those cells to concentrate iodide from plasma and might offer the ability to treat prostate cancer with radioiodine. Therefore, the aim of our study was to achieve tissue-specific expression of full-length human NIS (hNIS) cDNA in the androgen-sensitive human prostatic adenocarcinoma cell line LNCaP and in subcell lines C4, C4-2, and C4-2b in vitro. For this purpose, an expression vector was generated in which full-length hNIS cDNA coupled to the prostate-specific antigen (PSA) promoter has been ligated into the pEGFP-1 vector (NIS/PSA-pEGFP-1). The PSA promoter is responsible for androgen-dependent expression of PSA in benign and malignant prostate cells and was therefore used to mediate androgen-dependent prostate-specific expression of NIS. In addition, two control vectors were designed, which consist of the pEGFP-1 vector containing the PSA promoter without NIS cDNA (PSA-pEGFP-1) and NIS cDNA without the PSA promoter (NIS-pEGFP-1). Prostate cancer cells were transiently transfected with each of the above-described expression vectors, incubated with or without androgen (mibolerone) for 48 h, and monitored for iodide uptake activity. In addition, stably transfected LNCaP cell lines were established for each vector. Prostate cells transfected with NIS/PSA-pEGFP-1 showed perchlorate-sensitive, androgen-dependent iodide uptake in a range comparable to that observed in control cell lines transfected with hNIS cDNA. Perchlorate-sensitive iodide uptake was not observed in cells transfected with NIS/PSA-pEGFP-1 and treated without androgen or in cells transfected with the control vectors. In addition, prostate cancer cell lines without PSA expression (PC-3 and DU-145) did not show iodide uptake activity when transfected with NIS/PSA-pEGFP-1. Western blotting of LNCaP and C4-2b cell membranes transfected with NIS/PSA-pEGFP-1 using a monoclonal antibody that recognizes the COOH-terminus of hNIS revealed a band with a molecular weight of 90,000 that was not detected in androgen-deprived cells or in cells transfected with the control vectors, as well as a minor band at Mr 150,000 in transiently transfected LNCaP cell membranes. In conclusion, tissue-specific androgen-dependent iodide uptake activity has been induced in prostate cancer cells by PSA promoter-directed NIS expression. This study represents an initial step toward therapy of prostate cancer with radioiodine.
 ...
PMID:Prostate-specific antigen (PSA) promoter-driven androgen-inducible expression of sodium iodide symporter in prostate cancer cell lines. 1023

Causing prostate cancer cells to express functionally active sodium iodide symporter (NIS) by targeted NIS gene transfer might offer the possibility of radioiodine therapy of prostate cancer. Therefore, we investigated radioiodine accumulation and therapeutic effectiveness of 131I in NIS-transfected prostate cancer cells in vitro and in vivo. The human prostatic adenocarcinoma cell line LNCaP was stably transfected with NIS cDNA under the control of the prostate-specific antigen promoter. The stably transfected LNCaP cell line NP-1 showed perchlorate-sensitive, androgen-dependent iodide uptake in vitro that resulted in selective killing of these cells by 131I in an in vitro clonogenic assay. Xenografts were established in athymic nude mice and imaged using a gamma camera after i.p. injection of 500 microCi of 123I. In contrast to the NIS-negative control tumors (P-1) which showed no in vivo uptake of 123I, NP-1 tumors accumulated 25-30% of the total 123I administered with a biological half-life of 45 h. In addition, NIS protein expression in LNCaP cell xenografts was confirmed by Western blot analysis and immunohistochemistry. After a single i.p. application of a therapeutic 131I dose (3 mCi), significant tumor reduction was achieved in NP-1 tumors in the therapy group compared with P-1 tumors and tumors in the control group. In conclusion, a therapeutic effect of 131I has been demonstrated in prostate cancer cells after induction of tissue-specific iodide uptake activity by prostate-specific antigen promoter-directed NIS expression in vitro and in vivo. This study demonstrates the potential of NIS as a novel therapeutic gene for nonthyroidal cancers, in particular prostate cancer.
 ...
PMID:Treatment of prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide symporter. 1110 23

The sodium iodide symporter (NIS) mediates iodide uptake in thyroid cells and enables the effective radioiodide treatment of thyroid cancers. There is much interest in facilitating radioiodide therapy in other cancers by NIS gene transfer. This study showed that exogenous NIS expression decreased MATLyLu rat prostatic adenocarcinoma cell growth. Tumor growth and metastatic progression were significantly delayed in syngeneic rats injected with mixed or clonal populations of MATLyLu-NIS cells compared to rats with control tumors. MATLyLu-NIS tumors in nude mice had a lower, albeit not statistically significant, growth rate than control tumors. The Ki-67 labeling index in NIS-positive areas was lower than in NIS-negative areas of rat tumors derived from a mixed population of MATLyLu-NIS cells. Growth of clonal populations of MATLyLu-NIS cells was delayed in vitro. These results demonstrate that NIS expression inhibits MATLyLu cell growth, thereby providing an additional potential benefit of NIS-mediated gene therapy for cancer.
 ...
PMID:Effect of exogenous human sodium iodide symporter expression on growth of MATLyLu cells. 1269 87

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 (131)I 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(-6) M) in the presence of 10(-9) M mibolerone (mib). In addition, NIS functional activity was measured by iodide uptake assay, and in vitro cytotoxicity of (131)I 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(-6) M), indicating that it is androgen receptor dependent. The selective killing effect of (131)I in NP-1 cells was 50% in NP-1 cells incubated with 10(-9) M mib. This was increased to 90% in NP-1 cells treated with atRA (10(-7) M) plus 10(-9) M mib. In conclusion, treatment with atRA increases NIS expression levels and selective killing effect of (131)I 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.
 ...
PMID:Retinoic acid-induced stimulation of sodium iodide symporter expression and cytotoxicity of radioiodine in prostate cancer cells. 1286 21

The Na(+)/I(-) symporter (NIS) is the plasma membrane glycoprotein that mediates the active uptake of I(-) in the thyroid, ie, the crucial first step in thyroid hormone biosynthesis. NIS also mediates I(-) uptake in other tissues, such as salivary glands, gastric mucosa, and lactating (but not nonlactating) mammary gland. The ability of thyroid cancer cells to actively transport I(-) via NIS provides a unique and effective delivery system to detect and target these cells for destruction with therapeutic doses of radioiodide. Breast cancer is the only malignancy other than thyroid cancer to have been shown to functionally express NIS endogenously. The considerable potential diagnostic and therapeutic use of radioiodide in breast cancer is currently being assessed. On the other hand, exogenous NIS gene transfer has successfully been carried out into a variety of other cell lines and tumors, including A375 human melanoma tumors, and SiHa cervix cancer, human glioma, and hepatoma cell lines. Most notably, significant radioiodine therapy results have been obtained in the NIS-transfected human prostatic adenocarcinoma cell line LNCaP and in NIS-transfected myeloma cells, both of which exhibited prolonged retention of radio iodide even in the absence of I(-) organification. The therapeutic potential of alternative NIS-transported radioisotopes with different decay properties and a shorter, physical half-life than 131I(-), such as beta-emitter 188Rhenium (188ReO(4)-) and alpha-emitter 211Astatine (211At(-)), has been evaluated. In conclusion, it is clear that the remarkable progress made in the last few years in the molecular characterization of NIS has created new opportunities for the development of diagnostic and therapeutic applications for NIS in nuclear medicine.
 ...
PMID:The Na/I symporter (NIS): imaging and therapeutic applications. 1473 56