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SPITZWEG
Dexamethasone enhances the cytotoxic effect of radioiodine therapy in prostate cancer cells expressing the sodium iodide symporter.Scholz IV, Cengic N, Goke B, Morris JC, Spitzweg C J Clin Endocrinol Metab. 2004 Mar;89(3):1108-16.
"Recently, we have reported the induction of prostate-specific radioiodine accumulation in prostate cancer cells (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. The aim of our current study was to examine the regulation of PSA-promoter-directed NIS expression in NIS-transfected LNCaP cells (NP-1) by dexamethasone (Dex). For this purpose, NIS mRNA and protein expression levels were examined in NP-1 cells by Northern and Western blot analysis, respectively, after incubation with Dex (10(-8)-10(-6) M) in the presence of 10(-9) M mibolerone. NIS functional activity was measured by iodide uptake assay. In addition, we examined regulation of in vitro cytotoxicity of 131-I by Dex in an in vitro clonogenic assay. After incubation with Dex, iodide accumulation in NP-1 cells increased up to 1.5-fold, whereas NIS mRNA and protein expression levels were increased up to 1.7-fold. This effect of Dex was blocked by the androgen receptor antagonist casodex (10(-6) M). The killing effect of 131-I in NP-1 cells was increased from 55% when incubated with mibolerone alone to 95% when treated with Dex (10(-7) M) plus mibolerone. Treatment of NP-1 cells with Dex resulted in an additional antiproliferative effect as measured by clonogenic assay and nonradioactive proliferation assay. In conclusion, in addition to an antiproliferative effect, treatment with Dex increases androgen-dependent NIS mRNA and protein expression as well as iodide accumulation, resulting in an increased cytotoxic effect of 131-I in prostate cancer cells stably expressing NIS under the control of the PSA-promoter."
Probasin promoter (ARR(2)PB)-driven, prostate-specific expression of the human sodium iodide symporter (h-NIS) for targeted radioiodine therapy of prostate cancer.Kakinuma H, Bergert ER, Spitzweg C, Cheville JC, Lieber MM, Morris JC. Cancer Res. 2003 Nov 15;63(22):7840-4. Erratum in: Cancer Res. 2003 Dec 15;63(24):9057. Cancer Res. 2004 Feb 15;64(4):1559.
"Prostate cancer is one of the most promising candidates for sodium iodide symporter (NIS)-mediated gene therapy. Adenovirus-mediated expression of NIS that is driven by prostate-specific promoters induces generous radioiodine accumulation in prostate cancer cells that may be used for therapy with (131)I. We have recently developed a replication-deficient adenovirus carrying the human NIS cDNA linked to a composite probasin promoter, ARR(2)PB, aiming toward specific expression of the human NIS gene (h-NIS) in prostate tissue for targeted radioactive iodide therapy of prostate cancer (Ad-ARR(2)PB/hNIS). The ability of Ad-ARR(2)PB/hNIS to cause NIS expression in tumor cells was characterized by iodide uptake assay and compared with Ad-CMV/hNIS in which the h-NIS expression is driven by the cytomegalovirus (CMV) promoter. Androgen-dependent prostate cancer cell lines (LNCaP) and non-prostate origin tumor cell lines (SNU449, MCF-7, HCT116, OVCAR-3, and Panc-1) were infected with the viral constructs, and perchlorate-sensitive (125)I uptake and NIS protein expression were measured. Ad-ARR(2)PB/hNIS-infected LNCaP cells showed androgen-dependent and perchlorate-sensitive iodide uptake. Iodide accumulation in LNCaP cells infected with Ad-ARR(2)PB/hNIS, followed by incubation with synthetic androgen, was 5.3-fold increased compared with those coincubated with perchlorate (15,184 +/- 1,173 cpm versus 2,837 +/- 187 cpm). Ad-ARR(2)PB/hNIS-infected LNCaP cells revealed a 3.2-fold increase of iodide accumulation compared with those infected with Ad-CMV/hNIS (multiplicity of infection = 30). Iodide uptake in a panel of non-prostate tumor cell lines infected with Ad-ARR(2)PB/hNIS was no more than 2,500 cpm, demonstrating the tissue specificity of this construct. These results indicate that Ad-ARR(2)PB/hNIS can be used to achieve high-magnitude and tissue-specific expression of h-NIS in prostate tissue and is a promising candidate for cancer gene therapy of prostate cancer."
Retinoic acid-induced stimulation of sodium iodide symporter expression and cytotoxicity of radioiodine in prostate cancer cells.Spitzweg C, Scholz IV, Bergert ER, Tindall DJ, Young CY, Goke B, Morris JC. Endocrinology. 2003 Aug;144(8):3423-32.
"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."
In vivo sodium iodide symporter gene therapy of prostate cancer.Spitzweg C, Dietz AB, O'Connor MK, Bergert ER, Tindall DJ, Young CY, Morris JC. Gene Ther. 2001 Oct;8(20):1524-31. [abstract only]
"Radioiodine therapy, the most effective form of systemic radiotherapy available, is currently useful only for thyroid cancer because of thyroid-specific expression of the sodium iodide symporter (NIS). Here we explore the efficacy of a novel form of gene therapy using adenovirus-mediated in vivo NIS gene transfer followed by (131)I administration for treatment of prostate cancer. Prostate cancer xenografts in nude mice injected with an adenovirus carrying the NIS gene linked to the cytomegalovirus (CMV) promoter revealed highly active uptake of radioiodine. Following administration of 3 mCi of (131)I, we observed an average tumor volume reduction of 84 +/- 12%. These results show for the first time that in vivo NIS gene delivery into non-thyroidal tumors is capable of inducing accumulation of therapeutically effective radioiodine doses and might therefore represent an effective and potentially curative therapy for prostate cancer."
Gene therapy for prostate cancer: current status and future prospects.Harrington KJ, Spitzweg C, Bateman AR, Morris JC, Vile RG. J Urol. 2001 Oct;166(4):1220-33. Review. [abstract only]
"PURPOSE: Locally advanced,
relapsed and metastatic prostate cancer has a dismal prognosis with
conventional therapies offering no more than palliation. In recent
years advances achieved in understanding the molecular biology of
cancer have afforded clinicians and scientists the opportunity to
develop a range of novel genetic therapies for this disease. MATERIALS
AND METHODS: We performed a detailed review of published reports of
gene therapy for prostate cancer. Particular emphasis was placed on
recent developments in the arena of nonviral (plasmid DNA, DNA coated
gold particles, liposomes and polymer DNA complexes) and viral
(adenovirus, retrovirus, adeno-associated virus, herpes virus and pox
virus) vectors. Therapeutic strategies were categorized as corrective,
cytoreductive and immunomodulatory gene therapy for the purpose of
data analysis and comparison. RESULTS: Locoregional administration of
nonviral and viral vectors can yield impressive local gene expression
and therapeutic effects but to our knowledge no efficient systemically
delivered vector is available to date. Corrective gene therapy to
restore normal patterns of tumor suppressor gene (p53, Rb, p21 and
p16) expression or negate the effect of mutated tumor promoting
oncogenes (ras, myc, erbB2 and bcl-2) have efficacy in animal models
but this approach suffers from the fact that each cancer cell must be
targeted. A wide variety of cytoreductive strategies are under
development, including suicide, anti-angiogenic, radioisotopic and
pro-apoptotic gene therapies. Each approach has strengths and
weaknesses, and may best be suited for use in combination.
Immunomodulatory gene therapy seeks to generate an effective local
immune response that translates to systemic antitumor activity.
Currently most studies involve immunostimulatory cytokine genes, such
as granulocyte-macrophage colony-stimulating factor, or interleukin-2
or 12. CONCLUSIONS: Various therapeutic genes have proved activity
against prostate cancer in vitro and in vivo. However, the chief
challenge facing clinical gene therapy strategies is the lack of
efficient gene delivery by local and systemic routes. For the
foreseeable future vector development may remain a major focus of
ongoing research. Despite this caveat it is anticipated that gene
therapy approaches may significantly contribute to the management of
prostate cancer in the future."
Treatment of prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide symporter.Spitzweg C, O'Connor MK, Bergert ER, Tindall DJ, Young CY, Morris JC. Cancer Res. 2000 Nov 15;60(22):6526-30.
"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."
Prostate-specific antigen (PSA) promoter-driven androgen-inducible expression of sodium iodide symporter in prostate cancer cell lines.Spitzweg C, Zhang S, Bergert ER, Castro MR, McIver B, Heufelder AE, Tindall DJ, Young CY, Morris JC. Cancer Res. 1999 May 1;59(9):2136-41.
"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."
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