Abstract
As of January 2005, there were 1020 gene therapy clinical trials ongoing worldwide with 675 or 66.2% devoted to cancer gene therapy. The majority are occurring in the US and Europe (http://www.wiley.co.uk/genetherapy/clinical/). At the present time, to our knowledge there are no trials that employ gene delivery of Fas Ligand (FasL). As an important note, and in contrast to somatic cell therapy trials, there are no reported deaths due to therapeutic vector administration in any cancer gene therapy trial. That said, from our studies and from the published literature, the issue of gene delivery remains the major obstacle to successfully employing gene therapy for cancer treatment. Numerous laboratories are studying this with many different approaches. My co-workers and I have focused on the delivery issue by using various approaches that address tumor targeting and transgene expression. In addition, we are focusing on enhancing tumor cell killing via the bystander effect and through use of small molecules to enhance bystander activity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rubinchik S, Wang D, Yu H, Fan F, Luo M, Norris JS et al. A complex adenovirus vector that delivers FASL-GFP with combined prostate-specific and tetracycline-regulated expression. Mol Ther 2001; 4: 416–426.
Norris JS, Holman DH, Hyer ML, Bielawska A, El-Zawahry A, Chalfant C et al. Death receptors in cancer therapy. In: El-Deiry WS (ed). Ceramide, Ceramidase and FasL Gene Therapy in Prostate Cancer. Humana Press Inc.: Totowa, NJ, 2004, pp 323–338.
Holman DH, Hyer ML, El-Zawahry AM, Keller GM, Norris JS . Cancer gene therapy. In: Curiel DT, Douglas J (eds). Pro-Apoptotic Strategy in Cancer Gene Therapy. Humana Press Inc: Totowa, NJ, 2003, pp 273–286.
Voelkel-Johnson C, King DL, Norris JS . Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL. Cancer Gene Ther 2002; 9: 164–172.
Sudarshan S, Holman DH, Hyer ML, Voelkel-Johnson C, Dong JY, Norris JS . In vitro efficacy of Fas ligand gene therapy for the treatment of bladder cancer. Cancer Gene Ther 2005; 12: 12–18.
Rubinchik S, Yu H, Woraratanadharm J, Voelkel-Johnson C, Norris JS, Dong JY . Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector. Cancer Gene Ther 2003; 10: 814–822.
Lowe SL, Rubinchik S, Honda T, McDonnell TJ, Dong JY, Norris JS . Prostate-specific expression of Bax delivered by an adenoviral vector induces apoptosis in LNCaP prostate cancer cells. Gene Therapy 2001; 8: 1363–1371.
Hyer ML, Voelkel-Johnson C, Rubinchik S, Dong J, Norris JS . Intracellular Fas ligand expression causes Fas-mediated apoptosis in human prostate cancer cells resistant to monoclonal antibody-induced apoptosis. Molecular Ther 2000; 2: 348–358.
Rubinchik S, Ding R, Qiu AJ, Zhang F, Dong J . Adenoviral vector which delivers FasL-GFP fusion protein regulated by the tet-inducible expression system. Gene Ther 2000; 7: 875–885.
Zhang J, Thomas TZ, Kasper S, Matusik RJ . A small composite probasin promoter confers high levels of prostate-specific gene expression through regulation by androgens and glucocorticoids in vitro and in vivo. Endocrinology 2000; 141: 4698–4710.
Kasper S, Rennie PS, Bruchovsky N, Lin L, Cheng H, Snoek R et al. Selective activation of the probasin androgen-responsive region by steroid hormones. J Mol Endocrinol 1999; 22: 313–325.
Gossen M, Bujard H . Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 1992; 89: 5547–5551.
Rubinchik S, Norris JS, Dong JY . Construction, purification and characterization of adenovirus vectors expressing apoptosis-inducing transgenes. Methods Enzymol 2002; 346: 529–547.
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 Therapy 2001; 8: 247–253.
Noteborn MH . Chicken anemia virus induced apoptosis: underlying molecular mechanisms. Veterinary Microbiol 2004; 98: 89–94.
Guelen L, Paterson H, Gaken J, Meyers M, Farzaneh F, Tavassoli M . TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells. Oncogene 2004; 23: 1153–1165.
Hyer ML, Sudarshan S, Schwartz DA, Hannun YA, Dong J-Y, Norris JS . Quantification and characterization of the bystander effect in prostate cancer cells following adenovirus-mediated FasL expression. Cancer Gene Ther 2003; 10: 330–339.
EL-Ojeimy S, McKillop JC, El-Zawahry AM, Holman DH, Liu X, Schwartz DA et al. FasL gene therapy: a new therapeutic modality for head and neck cancer. Cancer Gene Ther 2006 (in press).
El-Zawahry A, Sudarshan S, Holman DH, Rashwan H, Bissada N, Dong J-Y et al. Fas Ligand gene therapy for renal cell carcinoma. 2006 (Manuscript in preparation).
Arai H, Gordon D, Nabel EG, Nabel GJ . Gene transfer of Fas ligand induces tumor regression in vivo. Proc Natl Acad Sci USA 1997; 94: 13862–13867.
Jian-Jun C, Yongnian S, Nabel GJ . Regulation of the proinflammatory effects of fas ligand. Science 1998; 282: 1714–1717.
Hyer ML, Sudarshan S, Kim Y, Reed JC, Dong JY, Schwartz DA et al. Downregulation of c-FLIP sensitizes DU145 prostate cancer cells to Fas-mediated apoptosis.[see comment]. Cancer Biol Ther 2002; 1: 401–406.
Kelly MM, Hoel BD, Voelkel-Johnson C . Doxorubicin pretreatment sensitizes prostate cancer cell lines to TRAIL induced apoptosis which correlates with the loss of c-FLIP expression.[see comment]. Cancer Biol Ther 2002; 1: 520–527.
Norris JS, Norris KL, Holman DH, El-Zawahry A, Keane TE, Dong J-Y et al. The present and future for gene and viral therapy of directly accessible prostate and squamous cell cancers of the head and neck. Future Oncol 2004; 1: 1–9.
Liu X, El-Zawahry AM, Holman DH, EL-Ojeimy SN, Bielawska A, Bielawski J et al. Modulation of ceramide metabolism enhances viral protein apoptin's cytotoxicity in prostate cancer. Mol Ther 2006; Accepted, pending revisions.
Hannun YA, Luberto C . Ceramide in the eukaryotic stress response. Trends Cell Biol 2000; 10: 73–80.
Ogretmen B, Hannun YA . Biologically active sphingolipids in cancer pathogenesis and treatment. Nat rev Cancer 2004; 4: 604–616.
Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind S et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 1996; 381: 800–803.
Kluk MJ, Hla T . Signaling of sphingosine-1-phosphate via the S1P/EDG-family of G-protein-coupled receptors. Biochim Biophys Acta 2002; 1582: 72–80.
Johnson KR, Johnson KY, Becker KP, Bielawski J, Mao C, Obeid LM . Role of human sphingosine-1-phosphate phosphatase 1 in the regulation of intra- and extracellular sphingosine-1-phosphate levels and cell viability. J Biol Chem 2003; 278: 34541–34547.
Hla T . Signaling and biological actions of sphingosine 1-phosphate. Pharmacol Res 2003; 47: 401–407.
Chalfant CE, Szulc Z, Roddy P, Bielawska A, Hannun YA . The structural requirements for ceramide activation of serine-threonine protein phosphatases. J Lipid Res 2004; 45: 496–506.
Chalfant CE, Rathman K, Pinkerman RL, Wood RE, Obeid LM, Ogretmen B et al. De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J Biol Chem 2002; 277: 12587–12595.
Chalfant CE, Ogretmen B, Galadari S, Kroesen BJ, Pettus BJ, Hannun YA . FAS activation induces dephosphorylation of SR proteins; dependence on the de novo generation of ceramide and activation of protein phosphatase 1. J Biol Chem 2001; 276: 44848–44855.
Chalfant CE, Kishikawa K, Mumby MC, Kamibayashi C, Bielawska A, Hannun YA . Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid. J Biol Chem 1999; 274: 20313–20317.
Seelan RS, Qian C, Yokomizo A, Bostwick DG, Smith DI, Liu W . Human acid ceramidase is overexpressed but not mutated in prostate cancer. Genes Chromosomes Cancer 2000; 29: 137–146.
Holman DH, El-Zawahry A, Elojeimy S, Liu X, Bielawski J, Szulc ZM et al. Lysosomotropic B13 analog induces apoptosis in prostate cancer cells involving JNK/AP-1, p53/p73, and Bcl-2 family members. Mol Cancer Therapeut 2006; Submitted for publication.
Acknowledgements
Special thanks to Janie Nelson for producing the drawing for this paper and for secretarial assistance. Both normal and cancerous tissues were obtained from the Hollings Cancer Center Tumor Bank. Supported by NIH/NCI PO1 CA97132 and 1R24 CA82933.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Norris, J., Bielawska, A., Day, T. et al. Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report. Cancer Gene Ther 13, 1045–1051 (2006). https://doi.org/10.1038/sj.cgt.7700965
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.cgt.7700965
Keywords
This article is cited by
-
Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response
Journal of Experimental & Clinical Cancer Research (2022)
-
Induction of apoptosis in prostate cancer cells by the novel ceramidase inhibitor ceranib-2
In Vitro Cellular & Developmental Biology - Animal (2015)
-
Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment
Cancer Immunology, Immunotherapy (2015)
-
Acid ceramidase induces sphingosine kinase 1/S1P receptor 2-mediated activation of oncogenic Akt signaling
Oncogenesis (2013)
-
Autophagy is increased in prostate cancer cells overexpressing acid ceramidase and enhances resistance to C6 ceramide
Prostate Cancer and Prostatic Diseases (2011)