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Lu Y, Madu CO. Viral-based gene delivery and regulated gene expression for targeted cancer therapy. Expert Opin Drug Deliv 2010; 7:19-35. [PMID: 19947888 DOI: 10.1517/17425240903419608] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
IMPORTANCE OF THE FIELD Cancer is both a major health concern and a care-cost issue in the US and the rest of the world. It is estimated that there will be a total of 1,479,350 new cancer cases and 562,340 cancer deaths in 2009 within the US alone. One of the major obstacles in cancer therapy is the ability to target specifically cancer cells. Most existing chemotherapies and other routine therapies (such as radiation therapy and hormonal manipulation) use indiscriminate approaches in which both cancer cells and non-cancerous surrounding cells are treated equally by the toxic treatment. As a result, either the cancer cell escapes the toxic dosage necessary for cell death and consequently resumes replication, or an adequate lethal dose that kills the cancer cell also causes the cancer patient to perish. Owing to this dilemma, cancer- or organ/tissue-specific targeting is greatly desired for effective cancer treatment and the reduction of side effect cytotoxicity within the patient. AREAS COVERED IN THIS REVIEW In this review, the strategies of targeted cancer therapy are discussed, with an emphasis on viral-based gene delivery and regulated gene expression. WHAT THE READER WILL GAIN Numerous approaches and updates in this field are presented for several common cancer types. TAKE HOME MESSAGE A summary of existing challenges and future directions is also included.
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Affiliation(s)
- Yi Lu
- University of Tennessee Health Science Center, Department of Pathology and Laboratory Medicine, Cancer Research Building, Room 218, 19 South Manassas Street, Memphis, TN 38163, USA.
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2
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Current status of experimental therapeutics for prostate cancer. Cancer Lett 2008; 266:116-34. [DOI: 10.1016/j.canlet.2008.02.065] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2007] [Revised: 02/22/2008] [Accepted: 02/22/2008] [Indexed: 11/17/2022]
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3
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Wang Y, Wang H, Li CY, Yuan F. Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery. Mol Cancer Ther 2006; 5:362-6. [PMID: 16505110 DOI: 10.1158/1535-7163.mct-05-0266] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Recent studies have shown that up to 90% of viral vectors could disseminate to normal organs following intratumoral infusion. The amount of dissemination might be dependent on the infusion conditions. Therefore, we investigated the effects of infusion rate, volume, and dose on transgene expression in liver and tumor tissues after intratumoral infusion of an adenoviral vector encoding luciferase. Luciferase expression was determined through bioluminescence intensity measurement. We observed that the luciferase expression in the liver was independent of the infusion rate but increased with the infusion dose, whereas the luciferase expression in the tumor was a bell-shaped function of the infusion rate. The latter observation was consistent with the distribution pattern of Evans blue-labeled albumin after its solution was infused into tumors at the same infusion rates. We also observed that the infusion volume could affect luciferase expression in the tumor but not in the liver. These observations implied that virus dissemination was determined mainly by the infusion dose, whereas the amount of transgene expression in the tumor depended on the distribution volume of viral vectors in the tumor as well as the infusion dose.
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Affiliation(s)
- Yong Wang
- Department of Biomedical Engineering, 136 Hudson Hall, Box 90281, Duke University, Durham, NC 27708, USA
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4
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Dwyer RM, Schatz SM, Bergert ER, Myers RM, Harvey ME, Classic KL, Blanco MC, Frisk CS, Marler RJ, Davis BJ, O'Connor MK, Russell SJ, Morris JC. A Preclinical Large Animal Model of Adenovirus-Mediated Expression of the Sodium–Iodide Symporter for Radioiodide Imaging and Therapy of Locally Recurrent Prostate Cancer. Mol Ther 2005; 12:835-41. [PMID: 16054438 DOI: 10.1016/j.ymthe.2005.05.013] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2005] [Revised: 05/10/2005] [Accepted: 05/29/2005] [Indexed: 10/25/2022] Open
Abstract
The sodium-iodide symporter (NIS) is primarily a thyroid protein, providing for the accumulation of iodide for biosynthesis of thyroid hormones. Native NIS expression has made possible the use of radioactive iodide to image and treat thyroid disease successfully. The current study, using adult male beagle dogs, was carried out in preparation for a Phase I clinical trial of adenovirus-mediated NIS gene (approved symbol SLC5A5) therapy for prostate cancer. Direct intraprostatic injection of virus (Ad5/CMV/NS) was followed by iv injection of 3 mCi 123I and serial image acquisition. The dogs were then given a therapeutic dose of 131I (116 mCi/m2) and observed for 7 days. SPECT/CT fusion imaging revealed clear images of the NIS-transduced prostates. Dosimetry calculations revealed an average absorbed dose to the prostate of 23 +/- 42 cGy/mCi 131I, with acceptably low radiation doses to other organs. This study demonstrated the successful introduction of localized NIS expression in the prostate gland of dogs, with no vector-related toxicity observed. None of the animals experienced any surgical complications, and serum chemistry panels showed no significant change following therapy. The results presented provide further evidence of the safety and efficacy of NIS as a therapeutic gene and support translation of this work into the clinical setting.
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Affiliation(s)
- Roisin M Dwyer
- Department of Endocrinology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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Abstract
Prostate cancer is one of the commonest causes of illness and death from cancer. Radical prostatectomy, radiotherapy, and hormonal therapy are the main conventional treatments. However, gene therapy is emerging as a promising adjuvant to conventional strategies, and several clinical trials are in progress. Here, we outline several approaches to gene therapy for prostate cancer that have been investigated. Methods of gene delivery are described, particularly those that have commonly been used in research on prostate cancer. We discuss efforts to achieve tissue-specific gene delivery, focusing on the use of tissue-specific gene promoters. Finally, the present use of gene therapy for prostate cancer is evaluated. The ability to deliver gene-therapy vectors directly to prostate tissue, and to regulate gene expression in a tissue-specific manner, offers promise for the use of gene therapy in prostate cancer.
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Affiliation(s)
- Ruth Foley
- Department of Haematology and Oncology, Institute of Molecular Medicine, St James' Hospital and Trinity College, Dublin, Ireland
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6
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Xu L, Zhao Y, Zhang Q, Li Y, Xu Y. Regulation of transgene expression in muscles by ultrasound-mediated hyperthermia. Gene Ther 2004; 11:894-900. [PMID: 15029231 DOI: 10.1038/sj.gt.3302254] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2003] [Accepted: 01/21/2004] [Indexed: 11/08/2022]
Abstract
Heat-sensitive transgene expression systems have been proposed recently for use in gene therapy to enable both spatial and temporal control of the gene activity. The transgene was put under the control of HSP-related promoters and could be turned on by external heat treatment. While the 'heat activation' phenomenon of the HSP-related promoters in vitro had been well documented, the detailed time response and temporal regulation profile in vivo were not fully understood. We reported here the regulation of transgene luciferase expression in vivo in muscles using a custom-built ultrasound-mediated hyperthermia instrument. The effects of different heating parameters and treatment regimens were evaluated. Optimal activation of gene expression was found at 39 degrees C. Significant tissue damage was observed at 41 degrees C and above, which directly correlated with the greatly reduced gene expression. The gene constructs remained stable and silent in muscle cells, and could be turned on at a later time without losing much activity. Repeated activation was also possible, but required heat treatment at a higher temperature to overcome thermotolerance.
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Affiliation(s)
- L Xu
- School of Pharmacy, Shanghai JiaoTong University, Shanghai, People's Republic of China
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7
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Abstract
The field of cancer gene therapy is in continuous expansion, and technology is quickly moving ahead as far as gene targeting and regulation of gene expression are concerned. This review focuses on the endocrine aspects of gene therapy, including the possibility to exploit hormone and hormone receptor functions for regulating therapeutic gene expression, the use of endocrine-specific genes as new therapeutic tools, the effects of viral vector delivery and transgene expression on the endocrine system, and the endocrine response to viral vector delivery. Present ethical concerns of gene therapy and the risk of germ cell transduction are also discussed, along with potential lines of innovation to improve cell and gene targeting.
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Affiliation(s)
- Luisa Barzon
- Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, I-35121 Padua, Italy
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8
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Park HS, Cheon J, Cho HY, Ko YH, Bae JH, Moon DG, Kim JJ. In vivo characterization of a prostate-specific antigen promoter-based suicide gene therapy for the treatment of benign prostatic hyperplasia. Gene Ther 2003; 10:1129-34. [PMID: 12808443 DOI: 10.1038/sj.gt.3301972] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
To develop a novel gene therapeutic modality for the effective treatment of benign prostatic hyperplasia (BPH), we investigated the properties of toxic gene therapy utilizing prostate-specific antigen (PSA) promoter driving herpes simplex virus thymidine kinase (HSV-TK) suicide gene to induce highly selective molecular ablation of epithelial cells with minimal systemic toxicity in canine prostate. Replication-defective recombinant adenoviral vectors containing HSV-TK gene under transcriptional control of long PSA promoter (Ad-PSA-HSV-TK) were developed and delivered in an situ manner. Briefly, laparotomies were performed and Ad-PSA-HSV-TK (1 x 10(9) PFUs) was injected into the left lateral lobe of prostate only on days 1 and 7 with appropriate prodrug acyclovir in adult Beagle dogs. The therapeutic efficacy was evaluated on the 56th experimental day. The striking apoptosis of epithelial cells was identified in the treated left half of canine prostate on TUNEL assay. On immunohistochemical studies, there was markedly decreased number of PSA-secreting epithelial cells compared to control. Also significant atrophy of prostate glands, associated with dense infiltration of lymphocytes and plasma cells, was identified in the treated side. The PSA promoter-based suicide gene therapy induced highly selective and definite ablation of epithelial cells in benign canine prostate. Our novel approach could open opportunity of gene therapeutic modality for the treatment of clinical BPH.
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Affiliation(s)
- H S Park
- Department of Urology, Korea University College of Medicine, University Hospital, #126-1, 5Ka, Anam-dong, Sungbuk-Ku, Seoul 136-705, Republic of Korea
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Abstract
Cancer gene therapy has been one of the most exciting areas of therapeutic research in the past decade. In this review, we discuss strategies to restrict transcription of transgenes to tumour cells. A range of promoters which are tissue-specific, tumour-specific, or inducible by exogenous agents are presented. Transcriptional targeting should prevent normal tissue toxicities associated with other cancer treatments, such as radiation and chemotherapy. In addition, the specificity of these strategies should provide improved targeting of metastatic tumours following systemic gene delivery. Rapid progress in the ability to specifically control transgenes will allow systemic gene delivery for cancer therapy to become a real possibility in the near future.
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Affiliation(s)
- Tracy Robson
- School of Biomedical Sciences, University of Ulster, Newtownabbey, Co. Antrim, BT37 0QB, Northern Ireland, UK
| | - David G. Hirst
- School of Biomedical Sciences, University of Ulster, Newtownabbey, Co. Antrim, BT37 0QB, Northern Ireland, UK
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Kaminski JM, Nguyen K, Buyyounouski M, Pollack A. Prostate cancer gene therapy and the role of radiation. Cancer Treat Rev 2002; 28:49-64. [PMID: 12027414 DOI: 10.1053/ctrv.2002.0250] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Even though prostate cancer is detected earlier than in the pre-PSA era, prostate cancer is the second leading cause of cancer mortality in the American male. Prostate cancer therapy is not ideal, especially for high-risk localized and metastatic cancer; therefore, investigators have sought new therapeutic modalities such as angiogenesis inhibitors, inhibitors of the cell signaling pathway, vaccines, and gene therapy. Gene therapy has emerged as potential therapy for both localized and systemic prostate cancer. Gene therapy has been shown to work supra-additively with radiation in controlling prostate cancer in vivo. With further technological advances in radiation therapy, gene therapy, and the understanding of prostate cancer biology, gene therapy will potentially have an important role in prostate cancer therapy.
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Affiliation(s)
- J M Kaminski
- Department of Radiation Oncology, Fox Chase Cancer Center, 7701 Burolme Avenue, Philadelphia, PA 19111, USA.
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11
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Harrington KJ, Bateman AR, Melcher AA, Ahmed A, Vile RG. Cancer gene therapy: Part 1. Vector development and regulation of gene expression. Clin Oncol (R Coll Radiol) 2002; 14:3-16. [PMID: 11898782 DOI: 10.1053/clon.2001.0002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Kevin J Harrington
- CRC Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, London, UK.
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12
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Xu CT, Huang LT, Pan BR. Current gene therapy for stomach carcinoma. World J Gastroenterol 2001; 7:752-9. [PMID: 11819868 PMCID: PMC4695588 DOI: 10.3748/wjg.v7.i6.752] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2001] [Revised: 05/29/2001] [Accepted: 06/06/2001] [Indexed: 02/06/2023] Open
Affiliation(s)
- C T Xu
- Editorial Department, the Journal of Fourth Military Medical University, Xi'an, Shaanxi Province, China.
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13
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Harrington KJ, Spitzweg C, Bateman AR, Morris JC, Vile RG. Gene therapy for prostate cancer: current status and future prospects. J Urol 2001; 166:1220-33. [PMID: 11547047 DOI: 10.1016/s0022-5347(05)65742-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
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.
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Affiliation(s)
- K J Harrington
- Molecular Medicine Program and Department of Endocrinology, Mayo Clinic, Rochester, Minnesota, USA
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15
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Andriani F, Nan B, Yu J, Li X, Weigel NL, McPhaul MJ, Kasper S, Kagawa S, Fang B, Matusik RJ, Denner L, Marcelli M. Use of the probasin promoter ARR2PB to express Bax in androgen receptor-positive prostate cancer cells. J Natl Cancer Inst 2001; 93:1314-24. [PMID: 11535706 DOI: 10.1093/jnci/93.17.1314] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Adenovirus-mediated overexpression of the apoptosis-inducing protein Bax can induce apoptosis in prostate cancer cell lines. Constitutive overexpression of Bax could result in unwanted apoptosis in every site of accidental Bax accumulation in vivo. Therefore, we developed an adenoviral construct (Av-ARR2PB-Bax) in which the probasin promoter, modified to contain two androgen response elements, drives Bax expression. This promoter would be expected to limit expression of Bax to cells expressing the androgen receptor. METHODS A variety of androgen receptor (AR)-positive and -negative cell lines of prostatic or nonprostatic origin were infected with Av-ARR2PB-Bax or a control virus, Av-ARR2PB-CAT, in which the same promoter drives expression of the chloramphenicol acetyl transferase-reporter gene. Bax expression and apoptosis in vitro were assessed by western blot analysis. Tumor size and apoptosis in vivo were assessed after four weekly injections of Av-ARR2PB-Bax or Av-ARR2PB-CAT into subcutaneous LNCaP xenografts growing in uncastrated male mice. All statistical tests were two-sided. RESULTS Bax was overexpressed in an androgen-dependent way in AR-positive cell lines of prostatic origin but not in AR-positive cells of nonprostatic origin or in AR-negative cell lines of either prostatic or nonprostatic origin. The androgen dihydrotestosterone activated apoptosis in LNCaP cells infected with Av-ARR2PB-Bax but not in those infected with Av-ARR2PB-CAT. Av-ARR2PB-Bax-injected LNCaP xenograft tumors decreased in tumor size from 34.1 mm3 (95% confidence interval [CI] = 25.1 mm3 to 43.1 mm3) to 24.6 mm3 (95% CI = -2.5 mm3 to 51.7 mm3), but the difference was not statistically significant (P =.5). Tumors injected with Av-ARR2PB-CAT increased in size, from 28.9 mm3 (95% CI = 12.7 mm3 to 45.1 mm3) to 206 mm3 (95% CI = 122 mm3 to 290 mm3) (P =.002) and contained statistically significant more apoptotic cells (23.3% [95% CI = 21.1% to 25.6%] versus 9.5% [95% CI = 8.0% to 11.1]) (P<.001). CONCLUSIONS Av-ARR2PB-Bax induces androgen-dependent therapeutic apoptosis in vitro and in vivo by activating apoptosis in AR-positive cells derived specifically from prostatic epithelium and does not affect nonprostatic cells.
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Affiliation(s)
- F Andriani
- Department of Medicine, Baylor College of Medicine, and VA Medical Center, Houston, TX 77030, USA
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16
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Wu L, Matherly J, Smallwood A, Adams JY, Billick E, Belldegrun A, Carey M. Chimeric PSA enhancers exhibit augmented activity in prostate cancer gene therapy vectors. Gene Ther 2001; 8:1416-26. [PMID: 11571582 DOI: 10.1038/sj.gt.3301549] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2001] [Accepted: 07/06/2001] [Indexed: 11/08/2022]
Abstract
The native PSA enhancer and promoter confer prostate-specific expression when inserted into adenovirus vectors capable of efficient in vivo gene delivery, although the transcriptional activity is low. By exploiting properties of the natural PSA control regions, we have improved the activity and specificity of the prostate-specific PSA enhancer for gene therapy and imaging applications. Previous studies have established that androgen receptor (AR) molecules bind cooperatively to AREs in the PSA enhancer core (-4326 to -3935) and act synergistically with AR bound to the proximal promoter to regulate transcriptional output. To exploit the synergistic nature of AR action we generated chimeric enhancer constructs by (1) insertion of four tandem copies of the proximal AREI element; (2) duplication of enhancer core; or (3) removal of intervening sequences (-3744 to -2855) between the enhancer and promoter. By comparing to the baseline construct, PSE, containing the PSA enhancer (-5322 to -2855) fused to the proximal promoter (-541 to +12), the three most efficacious chimeric constructs, PSE-BA (insertion of ARE4), PSE-BC (duplication of core) and PSE-BAC (insertion of core and ARE4), are 7.3-, 18.9-, and 9.4-fold higher, respectively. These chimeric PSA enhancer constructs are highly androgen inducible and retain a high degree of tissue discriminatory capability. Initial biochemical studies reveal that the augmented activity of the chimeric constructs in vivo correlates with their ability to recruit AR and critical co-activators in vitro. The enhanced activity, inducibility and specificity of the chimeric constructs are retained in an adenoviral vector (Ad-PSE-BC-luc). Systemic administration of Ad-PSE-BC-luc into SCID mice harboring the LAPC-9 human prostate cancer xenografts shows that this prostate specific vector retained tissue discriminatory capability compared with a comparable cytomegalovirus (CMV) promoter driven vector.
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Affiliation(s)
- L Wu
- Department of Urology, UCLA School of Medicine, Box 951738, Los Angeles, CA 09095-1738, USA
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Rubinchik S, Lowe S, Jia Z, Norris J, Dong J. Creation of a new transgene cloning site near the right ITR of Ad5 results in reduced enhancer interference with tissue-specific and regulatable promoters. Gene Ther 2001; 8:247-53. [PMID: 11313797 DOI: 10.1038/sj.gt.3301364] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2000] [Accepted: 10/18/2000] [Indexed: 11/09/2022]
Abstract
Tissue-specific transgene expression is a valuable research tool and is of great importance in delivering toxic gene products with adenovirus vectors to tumors. Limiting cytotoxic gene expression to the target cells is highly desirable. While a number of successful applications of tissue- and tumor-specific gene expression using Ad vectors has been reported, cloning of some promoters into Ad vectors resulted in modulation or loss of tissue specificity. This phenomenon is likely the result of the interaction of E1A enhancer (and possibly other Ad sequences) with the promoter cloned in the E1 region. We have compared performance parameters of prostate-specific and tet-regulatable promoters in plasmids containing the terminal repeat sequences of Ad5 with or without the E1A enhancer. Subsequently, adenoviral vectors were constructed containing identical expression units either in the E1 region or near the right ITR, and tested in several cell lines. Here, we report that promoters placed near the right ITR of Ad5 retain higher selectivity and lower background expression in both plasmid and adenovirus vectors. We confirm that the E1A enhancer can interfere with the desired activity of nearby promoters, and describe an alternative transgene insertion site for construction of Ad vectors.
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Affiliation(s)
- S Rubinchik
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425-2230, USA
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Bateman AR, Harrington KJ, Melcher AA, Vile RG. Cancer gene therapy: developments to 2000. Expert Opin Investig Drugs 2000; 9:2799-813. [PMID: 11093354 DOI: 10.1517/13543784.9.12.2799] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Cancer, at the molecular level, continues to be more thoroughly understood. With this understanding comes the opportunity for innovative therapeutic intervention. Gene therapy remains an attractive concept to treat cancer. However, a number of gene therapy clinical trials have now been reported and it is clear that barriers remain before gene therapy gains widespread clinical application. This article outlines current directions and novel developments in the field of cancer gene therapy, which attempt to overcome these obstacles.
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Affiliation(s)
- A R Bateman
- Molecular Medicine Program, Mayo Foundation, Rochester, MN 55905, USA.
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Harrington KJ, Linardakis E, Vile RG. Transcriptional control: an essential component of cancer gene therapy strategies? Adv Drug Deliv Rev 2000; 44:167-84. [PMID: 11072113 DOI: 10.1016/s0169-409x(00)00093-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The therapeutic index of cancer gene therapy approaches will, at least in part, be dictated by the spatial and temporal control of expression of the therapeutic transgenes. Strategies which allow precise control of gene transcription are likely to play a crucial role in the future pre-clinical and clinical development of gene therapy. In this review, we discuss these issues as they relate to tissue and tumor specific promoters. In addition, the exciting opportunities offered by the development of regulated gene expression systems using small molecules, radiation and heat are reviewed. It is realistic to expect that the future offers the prospect of amalgamating elements of a number of these different systems in a co-ordinated gene delivery approach with the potential to increase the efficacy and reduce the toxicity of treatment.
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Affiliation(s)
- K J Harrington
- Molecular Medicine Program, Guggenheim 1836, Mayo Clinic, 200 1st Street SW, Rochester, MN 55902, USA
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Steiner MS, Wang Y, Zhang Y, Zhang X, Lu Y. p16/MTS1/INK4A suppresses prostate cancer by both pRb dependent and independent pathways. Oncogene 2000; 19:1297-306. [PMID: 10713671 DOI: 10.1038/sj.onc.1203428] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Tumor suppressor gene p16 is a cyclin-dependent kinase inhibitor and an important negative cell cycle regulator. The inactivation of p16 appears to be a common event in prostate cancer. Replacement of p16 inhibits prostate tumor cell growth, but the mechanism is not known. Human prostate cancer cell lines PPC-1, which has an inactivated p16, and DU145, which has a nonfunctional retinoblastoma Rb protein (pRb), were used to determine the possible mechanism of p16 mediated growth inhibition. PPC-1 cells treated with 5-aza-2'-deoxycytidine (5-aza-dC), a demethylating agent, induced p16 expression, inhibited cell growth, and induced senescence. Similarly, PPC-1 cells transduced by an adenoviral vector containing the p16 gene (AdRSVp16) produced a p16 protein that suppressed cellular proliferation and induced senescence. Co-staining of AdRSVp16-transduced PPC-1 cells by p16 immunohistochemistry and by beta-galactosidase substrate X-gal showed that the morphologically enlarged cells expressed both p16 and senescence-associated beta-galactosidase. In contrast, AdRSVp16 did not induce senescence in DU145 cells, but did inhibit its growth. However, when wild-type pRb was introduced in DU145 cells, AdRSVp16 was able to induce senescence. Thus, the mechanism by which p16 suppressed prostate cancer was dependent on the pRb functional status of cells whereby p16 caused pRb+ cells to undergo inhibition by senescence, whereas pRb- cells were also inhibited, but not by senescence.
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Affiliation(s)
- M S Steiner
- University of Tennessee Urologic Research Laboratories, Department of Urology, University of Tennessee-Memphis, Memphis, Tennessee 38163, USA
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