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REVIEW ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 1-5

Gene therapy in oral cancer – An update


Department of Oral and Maxillofacial Pathology and Oral Microbiology, Thai Moogambigai Dental College and Hospital, Chennai, Tamil Nadu, India

Date of Submission29-Nov-2019
Date of Acceptance13-Jan-2020
Date of Web Publication14-May-2020

Correspondence Address:
Dr. L J Sai Lakshmi
Thai Moogambigai Dental College, Golden George Nagar, Mogappair, Chennai, Tamil Nadu - 600 107
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JDRNTRUHS.JDRNTRUHS_114_19

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  Abstract 


Gene therapy is the use of DNA as an agent to treat genetic disorders. Gene therapy aims at the insertion of a therapeutic gene into the cells of a patient for the correction of an inborn error of metabolism, to alter or repair an acquired genetic abnormality. Today, most of the gene therapy studies are aimed at cancer and hereditary diseases which are linked to genetic defects. Cancer usually occurs due to the production of multiple mutations in a single cell which cause it to proliferate out of control. Several methods such as surgery, radiation therapy, and chemotherapy have been used widely to treat cancers, but recurrence is common in approximately one third of patients. To improve the treatment modality and to increase the survival rate, gene therapy can be used as an adjunct to other therapies for cancer patients. The purpose of this article is to review the concepts and technique, with an insight into the current research on its applications in oral squamous cell carcinoma (OSCC).

Keywords: Gene gun, gene therapy, oral cancer, vectors


How to cite this article:
Sai Lakshmi L J, Radhika T, Jeddy N. Gene therapy in oral cancer – An update. J NTR Univ Health Sci 2020;9:1-5

How to cite this URL:
Sai Lakshmi L J, Radhika T, Jeddy N. Gene therapy in oral cancer – An update. J NTR Univ Health Sci [serial online] 2020 [cited 2020 Aug 14];9:1-5. Available from: http://www.jdrntruhs.org/text.asp?2020/9/1/1/284196




  Introduction Top


OSCC is the most common malignancy in the oral cavity and is the 6th most common cancer world-wide.[1] Oral cancer is associated with genetic mutations resulting from exposure to tobacco, alcohol, betel quid, etc.[2] The current treatment strategies for OSCC include a combination of surgery, radiation therapy, and chemotherapy. Surgical resection of tumors cause significant functional (speech and swallowing) and cosmetic defects. Chemotherapy is associated with toxicity and has not been proved to possess an impact on the survival of patients. Recurrence is common in approximately one third of the patients despite definitive treatment. Gene therapy which involves replacement of the defective gene by a therapeutic gene has emerged as a promising treatment modality in the field of biomedicine.[3] This alternate treatment option has been proven to increase survival rates of OSCC patients. This review highlights current research methods available for combating OSCC.


  The History of Gene Therapy Top


Joshua Lederberg and Edward Tatum laid out the fundamentals for gene therapy.[4] Michael et al. succeeded in transferring a gene (TK gene, which codes for thymidine kinase) into mammalian cells in 1977.[5],[6] In the year 1990, the first approved gene therapy clinical trial took place when Ashanthi De Silva, a 4-year-old girl with Adenosine Deaminase (ADA)-deficiency/Severe Combined Immunodeficiency (SCID) syndrome, was given her own T cells engineered with a retroviral vector carrying a normal ADA gene by the NIH (National Institutes of Health) team of Anderson, Blaese, and Rosenberg.[7]

Concept of gene therapy

Gene therapy involves the transfer of a therapeutic gene into specific cells of an individual in order to repair a faulty gene. The objective of gene therapy is to introduce new genetic material into target cells without causing damage to the surrounding tissues and also treatment-related morbidity is decreased with gene therapy when compared with other methods.[8]

Types of gene therapy

There are two primary modes of gene therapy.

They are:-

  1. Somatic gene therapy
  2. Germ line gene therapy


In somatic gene therapy

, the therapeutic genes are introduced into somatic cells, which restricts the effects of the individual and are not passed on to the next generation.[9]

In germ line gene therapy

, either the sperm or egg can be altered by introducing the therapeutic gene, which gets integrated into the genome.[10]

Methods to deliver therapeutic genes

Therapeutic gene can be delivered to the target cells in two ways.

Ex vivo—Therapeutic gene can be inserted into cells from the affected tissue outside the body and then returned to the body.

In vivo—Therapeutic material is inserted directly into the affected site.

In oral cancer, in vivo approach is usually used because superficial lesions usually lend themselves to the direct injection of genetic material. For both of these methods, a delivery vehicle called a vector is used to introduce the therapeutic material into the patient's target cells (Blau and Springer, 1995).[3]

Vectors in gene therapy

The vector or carrier is used for the transfer of a therapeutic gene in to the recipient cells.[11]

Vectors are broadly comprised of two types:

  • Viral vectors.
  • Non-viral vectors.


Viral vectors

All viruses bind to their hosts and introduce genetic material into the host cell as part of the replication cycle.

Types of virus groups used as vectors are:

  • Retro virus
  • Herpes virus
  • Adeno virus
  • Adeno associated virus (AAV).[12]


Non-viral vectors

Various methods known are:

Physical methods

Electroporation

In this method, short pulses of high voltage is used to carry DNA across the cell membrane through temporary formation of pores in the cell membrane. The side-effect that could arise is the localized progressive necrosis leading to increase cell death. Newer method of electron-avalanche transfection involves efficient delivery of DNA through short pulses resulting in insertional efficiency and decreased cell damage.

  1. Gene gun


  2. DNA is coated with gold particles and is loaded into a device with generation of force to achieve penetration of DNA into cells leaving gold on the stopping disk.

  3. Sonoporation


  4. By using acoustic cavitation, it disrupts the cell membrane and allow DNA to move into cells.

  5. Magnetofecation


DNA is complexed with magnetic particles and a magnet is placed underneath the tissue culture dish to bring DNA complex into contact with a cell monolayer.


  Chemical Methods Top


Various chemical delivery systems include

  1. Oligonucleotides
  2. Lipoplexes and polyplexes
  3. Dendrimers
  4. Inorganic nanoparticles such as gold, silica and iron oxide are used for gene delivery.[9]


Techniques of gene therapy

The therapies that express gene products, which result in the death of cancer cells, include,

  • Gene addition therapy,
  • Gene excision therapy,
  • Antisense RNA therapy,
  • Immunotherapy,
  • Suicide gene therapy,
  • Gene therapy with the use of oncolytic viruses.


Gene addition therapy

Genetic alterations include mutations of p53, the Retinoblastoma Gene, p16 and p21. P53 is the most commonly used tumor suppressor gene in gene therapy and about 60% of tumors are associated with mutation of the p53 gene. In this technique, the tumor growth is controlled by the introduction of tumor suppressor genes which inactivates the carcinogenic cells.[13] p53 is the most commonly used gene with adenovirus as viral vectors. Studies are being carried out on adenovirus vector Ad5CMV-p53, which is first given by intramucosal injection followed 2 h later by a mouthwash. From the next day, it is administered as a mouthwash twice daily for 2-5 days and this treatment is repeated every 28 days. This technique inhibits disease progression in precancerous lesions with no toxic effects. Other tumor suppressor genes that could be introduced into tumor cells are Rb gene and mda-7.[14]

Gene excision therapy

This therapy inhibits tumor growth by removal of oncogenes. The genes that control growth and cell cycle progression, including some factors like- TGF-α1, PDGF-α and PTEN are regulated by the expression of the protein EGR-1. Thus, inhibiting this protein represents good therapeutic approach for the tumor cells. Some studies demonstrated that inhibition of the protein kinase C reduces the expression of this gene, triggering higher sensitivity of the tumor to radiotherapy (Okamura et al., 2002).[3]

Antisense RNA therapy

In this technique, remedial gene is introduced that prevents the expression of a specific defective gene is called as “Antisense therapy.” Gene expression can be inhibited by RNA that is complementary to the strand of DNA expressing the gene. This technique can be directed towards carcinoma cells whose malignant phenotype is dependent upon the expression of particular oncogenes such as Myc, Fos, and Ras. Inhibition of expression of these oncogenes may alter the phenotype, thus prevents the tumor growth.[15]

Immunologic gene therapy

Immunotherapy either increasing the immunogenic potential of tumor cells or the patient's immune response to tumor. Patients with OSCC show deficient function of several types of immune cells which include natural killer cells, T-lymphocytes and cytokines. The combined use of mIL – 2 (murine interleukin 2) and mIL -12 (murine interleukin -12) gene therapy resulted in significant reduction in the tumor due to increased activation of cytolytic T lymphocyte and natural killer cells. Radiosensitivity to γ radiation and chemosensitivity to 5-fluoracil (5-FU) in oral squamous cell carcinoma can be enhanced after suppression of NF-ĸB activity, which activates the antiapoptotic proteins TNF, TRAF-1, TRAF-2 and cIAP-1. The inhibition of NF-κB can decrease expression of proinflammatory cytokines, e.g. IL-1α, IL-6, and IL-8, and of enzymes that degrade matrix metalloproteinase -9 (MMP-9). The progression and metastasis of OSCC can be prevented by inhibiting NF-κB activity which may be a useful coadjuvant treatment in oral cancer therapy. Systemic administration of Anti-ICAM-2 induced the complete regression of OSCC. ICAM-2 is a glycosylated protein with surface adhesion that is expressed in endothelial cells and activated lymphocytes.[16]

Suicide gene therapy

This therapy involves enzymes, the expression of which transforms the non-toxicity producing drug into an active cytotoxic substance. It is the most commonly used gene therapy which uses thymidine kinase or other chemosensitizing genes (Gardlik et al., 2011). Thymidine kinase gene of Herpes Simplex Virus (HSV) transforms ganciclovir into ganciclovir phosphate. Gene transfer of HSVtk gene (Herpes simplex virus thymidine kinase gene) via adenovirus vector in combination with ganciclovir administration may be a good therapeutic option for OSCC. HSV-tk/GCV therapy in cultured oral squamous cancer cells have shown that tumor cell death occurs mainly by an apoptotic process and the observed high cytotoxicity is due to the bystander effect, which is promoted by the diffusion of the toxic agent into neighboring cells via gap junctions. The studies in syngeneic orthotopic and subcutaneous murine models for squamous cell carcinoma of the head and neck revealed that intratumoral administration of the HSV-tk gene mediated by transferrin- or folate-associated lipoplexes, followed by intraperitoneal injection of ganciclovir, results in a potent antitumor effect.[17]

Gene therapy with the use of oncolytic viruses

In this therapy, a vector (virus) is genetically modified, which replicates and lyses the tumor cells. For example, adenovirus mediated gene therapy is used for advanced cancers than traditional therapies.[7]

Various studies have been conducted to prove efficacy of gene therapy in oral cancer and precancer [Table 1].[18]
TABLE 1: Gene therapy approaches in oral cancer and precancer (adapted from sonia)[18]

Click here to view


Advantages

  • Gene therapy aids in the prevention against the potentially toxic effects in the body, which can be caused by other therapies.
  • It decreases the cost of various therapies and improves the patient's life style for a longer period.[19]


Disadvantages

  • Patients may have to undergo multiple rounds of gene therapy.
  • There is a possibility that the host's immune system and its response may reduce the effectiveness of the gene therapy.
  • The viral vectors can present a variety of potential problems to the patient, such as toxicity and immune and inflammatory responses.
  • Gene therapy is used to treat only single gene disorders.
  • A tumor can be induced if the DNA is introduced into a wrong place in the genome, for example, into a tumor suppressor gene.[19]



  Conclusion Top


Gene therapy is an emerging field of biomedicine, with a potential to form a definitive treatment for oral cancer and precancer by offering greater effectiveness and possibly reducing the mortality rate associated with these lesions. The research on gene therapy in oral cancer is increasing day by day, both in the laboratory and the clinical settings. In the future, combination of gene therapy with chemotherapy and immunotherapy may form one of the most promising fields of research in the management of oral cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Wigler M, Silverstein S, Lee LS, Pellicer A, Cheng Y, Axel R. Transfer of purified herpes virus thymidine kinase gene to cultured mouse cells. Cell 1977;11:223-32.  Back to cited text no. 5
    
6.
Anderson WF, Killos L, Sanders-Haigh L, Kretschmer PJ, Diacumakos EG. Replication and expression of thymidine kinase and human globin genes microinjected into mouse fibroblasts. Proc Nat Acad Sci USA 1980;77:5399-403.  Back to cited text no. 6
    
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Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T lymphocyte- directed gene therapy for ADA- SCID: Initial trial results after years. Science 1995;270:475-80.  Back to cited text no. 7
    
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Ayllón Barbellido S, Campo Trapero J, Cano Sánchez J, Perea García MA, Escudero Castaño N, Bascones Martínez A. Gene therapy in the management of oral cancer: Review of the literature. Med Oral Patol Oral Cir Bucal 2007;12:E549-51.  Back to cited text no. 8
    
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Indu S, Ramesh V, Oza N, Prashad KV. Gene therapy: An overview. J Orofacial Sci 2013;5:83-7.  Back to cited text no. 9
    
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Kumar MS, Masthan KM, Babu NA, Dash KC. Gene therapy in oral cancer: A review. J Clin Diagn Res 2013;7:1261-3.  Back to cited text no. 10
    
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Heera R, Beena VT, Simon R, Choudhary K. Gene therapy in oral cancer: An overview. Oral Maxillofac Pathol J 2010;1:976-1225.  Back to cited text no. 11
    
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Smith AE. Viral vectors in gene therapy. Annu Rev Microbiol 1995;49:807-38.  Back to cited text no. 12
    
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Saraswathi TR, Kavitha B, Vijayashree Priyadharsini J. Gene therapy for oral squamous cell carcinoma: An overview. Indian J Dent Res 2007;18:120-3.  Back to cited text no. 14
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Jacob KC, Yashoda R, Puranik MP. Gene therapy in the treatment and prevention of oral cancer: An overview. Int J Adv Health Sci 2015;2:14-20.  Back to cited text no. 15
    
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Sunil PM, Joseph I, Susan Varghese S. Gene therapy in oral squamous cell Carcinoma - A short review. Oral Maxillofac Pathol J 2011;2:976-1225.  Back to cited text no. 16
    
17.
Faneca H, Düzgüneş N, Pedroso de Lima MC. Suicide gene therapy for oral squamous cell carcinoma. Methods Mol Biol 2019;1895:43-55.  Back to cited text no. 17
    
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Kumar NA, Agrawal A, Sreedevi R. Novel therapy for oral cancer – Gene therapy an update. Br J Med Med Res 2015;9:1-8.  Back to cited text no. 18
    
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Sharma R, Khajuria R, Sharma CL, Kapoor B, Goswami KC, Kohli K. Gene therapy: Current concepts. JK Sci 2004;6:62-6.  Back to cited text no. 19
    



 
 
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