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Gene transfer-mediated intracellular photodynamic therapy

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Gene transfer-mediated intracellular photodynamic therapy
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  INTRODUCTION Photodynamic therapy (PDT) evaluated as a promisingmodality of cancer treatment (1–3) is based on injectionof photosensiting and in tumor localizing dyes followedby exposure of the tumor to intensive light source, usu-ally from a laser. Unfortunately, PDT is efficient only inthe cases where the entire tumor can be reached by light.Therefore tumors thicker than 4–5mm are not com-pletely eradicated by PDT. DISCUSSION Recently, a new method of PDT has been proposed (4),with the purpose of overcoming difficulties with expen-sive and inefficient laser sources. In this invention, thechemical compounds (e.g. luminol and oxidization com-pound), which are capable of producing light when theyreact, are separately encapsulated in heat-sensitive lipo-somes. Photosensitive dye is injected into the organism,followed by injection of liposome-encapsulated com-pounds into the same organism. The tumor region is thenheated up to melt liposomes to permit mixing of activa-tion components. In a series of experiments on animals,the efficiency of this approach to PDT was proved.Many different organism (e.g. firelies) have the capabil-ity to emit intensive light via protein luciferase that oxi-dize a substrate luciferin with formation of a molecule inan electronically excited state (5).As has been shown many mammalian cells may betransfected with cDNA encoding luciferase gene, and theemitted light produced by subsequent reaction of expressed luciferase with luciferin can easily be detectedboth in vitro and in vivo (10,11). Simple equipment waseven proposed to detect routinely the light using a single-photon counting tube (12). The emitted light is so inten-sive, that a single transfected luciferase-expressing cellmay be detected amongst over one million non-infectedcells. Luciferase gene now represents the most efficientmarker of gene expression in living cells.One of the most promising approaches for the treat-ment of cancer is gene therapy (6–9), especially suitablefor the brain tumors which arise from dividing cellswithin a background of essentially non-dividing cells.Retroviral vectors provide a useful vehicle for selectivetargeting, since they can only integrate into the genomeof dividing cells, there are no limitations in host range,and these vectors have already been used successfully toinfect many different cell types. Gene transfer-mediated intracellularphotodynamic therapy M. Babincová, 1 P. Sourivong, 2 P. Babinec 3 1 Department of Biophysics and Chemical Physics, Comenius University, Bratislava, Slovakia 2 Physics Department, University of North Dakota, Grand Fork, ND, USA3Department of Chemistry, Jackson State University,Jackson, MS, USA Summary The main limitation of photodynamic therapy is a very short penetrance length of the light in tissues. Toovercome this shortcoming, a new method is proposed, where first a gene encoding protein luciferase is deliveredusing, e.g. adenovirus vector to the neoplastic cells and, after its expression, the photosensitizer, which should beactivated, together with luciferin are injected to the organism. After their accumulation in the cancer cells, thephotosensitizer activation is accomplished via light produced by chemiluminiscent reaction of luciferase and luciferin. ©2000 Harcourt Publishers Ltd Received 18 August 1998 Accepted 8 December 1998 Correspondence to  : M. Babincová, Department of Biophysics and ChemicalPhysics, Comenius University, MFF UK, Mlynská dolina F1, 842 15Bratislava, Slovakia Fax: + 421 7 654 25 882;E-mail: babincova@fmph.uniba.sk 180 Medical Hypotheses  (2000) 54 (2), 180–181 ©2000 Harcourt Publishers LtdDOI: 10.1054/mehy.1999.0012, available online at http://www.idealibrary.com on  Gene transfer-mediated intracellular photodynamic therapy  181 ©2000 Harcourt Publishers LtdMedical Hypotheses (2000) 54  (2), 180–181 As a combination of PDT and gene therapy, we suggestthe following method of cancer treatment:1.transfection of neoplastic cells by firefly luciferasegene;2.injection of the photosensitizer (e.g.hematoporphyrine derivatives) which shouldpreferentially accumulate in the tumor;3.Injection of luciferin to the organism, which afterentering to the interior of neoplastic cells will produceintensive light, activating the photosensitizer alreadypresent in the cell;4.destruction of neoplastic cells by activatedphotosensitizer.The proposed method is very selective because onlyneoplastic cells would produce luciferase. Using variousmutants of luciferase (13), the wavelength of light may bechanged and various photosensitizers may be activated.The method can be improved also using various kinds of luciferin (14,15), with enhanced membrane permeabilityand enhanced capability to produce light. It should beremembered that there are more than 1800 species of firefly (16) and luciferases from various species may havedifferent properties and may be more suitable for someparticular kinds of cancer and/or photosensitizers.The delivery of photosensiting dye and luciferin to thetumor may be substantially enhanced using some carriersystems, e.g. magnetoliposomes (17). CONCLUSION Certain types of cancer, e.g. gliomas, which are the mostcommon primary tumor arising in the human brain, defythe current modalities of treatment. Despite surgery,chemotherapy, and radiotherapy, glioblastoma multi-forme, the most common of the gliomas, is almost univer-sally fatal. The only alternatives for their treatment arecurrently considered to be gene therapy or photody-namic therapy. Our method combines the advantages of both approaches and we hope that it may be useful forthe treatment of cancer and other diseases. REFERENCES 1.Dougherty T.J., Gomer C.J., Henderson B.W. et al. Photodynamictherapy.  J Natl Cancer Inst  1998; 90 : 889–905.2.Levy J.G., Obochi M. New applications in photodynamic therapy.Introduction. Photochem Photobiol  1996; 64 : 737–739.3.Popovic E.A., Kaye A.H., Hill J.S. Photodynamic therapy of braintumors.  J Clin Laser Med Surg  1996; 14 : 251–261.4.Dougherty T.J. In situ photodynamic therapy. US patent:5,257,970 (Nov. 1993).5.Hastings J.W. Chemistries and colors of bioluminiscentreactions: a review. Gene  1996; 173 : 5–11.6.Maria B.L., Friedman T. Gene therapy for pediatric brain tumors. Semin Pediat Neurol  1997; 4 : 333–339.7.Peltekian E., Parrish E., Bouchard C., Peschanski M., Lisovoski F.Adenovirus-mediated gene transfer to the brain:methodological assessment.  J Neurosci Methods  1997; 71 : 77–84.8.Dachs G.U., Dougherty G.J., Stratford I.J., Chaplin D.J. Targetinggene therapy to cancer: a review. Oncol Res  1997; 9 : 313–325.9.Kreuzer J., Denger S., Reifers F., et al. Adenovirus-assistedlipofection: efficient in vitro gene transfer of luciferase andcytosine deaminase to human smooth muscle cells. Atherosclerosis  1996; 124 : 49–60.10.Lorenz W.W., Cormier M.J., O’Kane D.J., Hua D., Escher A.A.,Szalay A.A. Expression of the Renilla reniformis  luciferase genein mammalian cells.  J Biolumin Chemilumin  1996; 11 : 31–37.11.Hooper C.E., Ansorge R.E., Browne H.M., Tomkins P. CCDimaging of luciferase gene in single mammalian cells.  J Biolumin Chemilumin  1990; 5 : 123–130.12.Gailey P.C., Miller E.J., Griffin G.D. Low-cost system for real-timemonitoring of luciferase gene expression. Biotechniques  1997; 22 : 528–534.13.Nakano E: Mutants of firefly luciferase which produce differentcolors of light. Tanpakushitsu Kukusan Koso  1992; 37  : 205–207.14.Craig F.F., Simmonds A.C., Watmore D., McCapra F., White M.R.Membrane-permeable luciferin esters for assay of fireflyluciferase in live intact cells. Biochem J  1996; 317  : 637–641.15.Lembert N. Firefly luciferase can use L-luciferin to producelight. Biochem J  1996; 317  : 273–277.16.Gould S.J., Subramani S. A firefly luciferase as a tool inmolecular and cell biology. Anal Biochem  1988; 175 : 5–13.17.Babincová M., Babinec P. Controlled drug delivery usingmagnetoliposomes. Cell Mol Biol Lett  1997; 2 : 1–10.
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