P53 Gene Therapy: A Potential Panacea To Cancer
By - 11/30/2007
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.jpg "Mr. Satish A. Polshettiwar")
Mr. Satish A. Polshettiwar
The extensive work focuses on gene therapy as a novel method to cure cancer [ovarian &breast], especially p53 gene having tremendous potential used as a suppressor gene to kill the tumor cells, their types, roles and use of p53.
It focuses on the mechanism of p53 apoptosis [programmed cell death]. It suggests advanced therapies in combination of chemotherapy with gene therapy. It also shed light on various current research viral & non viral vectors used in p53 gene therapy.
Introduction-
Cancer has been the most dreadful disease encompassing the world today. We focus on thancer in our world today .Various therapies like radiation , chemotherapy, surgery are used . Need can be felt to focus on the latest therapies. We focus on the gene therapy to treat not much discussed ovarian and breast cancers which now a days becoming serious cause of concern.
Types of ovarian cancers - Germ cell tumors ,
Rare tumors,
Sex cord tumors
Epithelial tumors -, .
Types of breast cancers - Ductal carcinoma 65-90%
Lobular carcinoma 10%
Inflammatory breast cancer
Medullary carcinoma of the breast 5%
Colloid carcinoma 2%
Papillary carcinoma 1%
Metaplastic carcinoma
Triple Negative Breast Cancer
Gene Therapy
What are tumor suppressor genes ?
Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, and tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer. About 30 tumor suppressor genes have been identified, including p53, BRCA1, BRCA2, APC, and RBI.
An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated (turned off). Another major difference is that while the overwhelming majority of oncogenes develop from mutations in normal genes (proto-oncogenes) during the life of the individual (acquired mutations), abnormalities of tumor suppressor genes can be inherited as well as acquired.
Types of Tumor Suppressor Genes
Genes that control cell division:
Some tumor suppressor genes help control cell growth and reproduction. The RB1 (retinoblastoma) gene is an example of such a gene. Abnormalities of the RB1 gene can lead to a type of eye cancer (retinoblastoma) in infants, as well as to other cancers.
Genes that repair DNA :
A second group of tumor suppressor genes is responsible for repairing DNA damage. Every time a cell prepares to divide into 2 new cells, it must duplicate its DNA. This process is not perfect, and copying errors sometimes occur. Fortunately, cells have DNA repair genes, which make proteins that proofread DNA. But if the genes responsible for the repair are faulty, then the DNA can develop abnormalities that may lead to cancer. When DNA repair genes don’t work, mutations can slip by, allowing oncogenes and abnormal tumor suppressor genes to be produced. The genes responsible for HNPCC (hereditary nonpolyposis colon cancer) are examples of DNA repair gene defects.
Cell "suicide" genes:
If there is too much damage to a cell’s DNA to be fixed by the DNA repair genes, the p53 tumor suppressor gene is responsible for destroying the cell by a process sometimes described as "cell suicide." Other names for this process are programmed cell death or apoptosis. If the p53 gene is not working properly, cells with DNA damage that has not been repaired continue to grow and can eventually become cancerous. Abnormalities of the p53 gene are sometimes inherited, such as in the Li-Fraumeni syndrome (LFS)..
P53:
As the name says this gene is made up of mass of 53kilodaton having composed of 393 amino acids located in 17th chromosome.
P53 + DNA ------- FORMATION OF P21 + cdK2 ------ Stop cell division
P35 {not bind } to DNA -------- tumor develops
Role of p53
- Growth arrest
- DNA repair
- Apoptosis – programmed cell death
- Gene marker
1) During apoptosis loss of the integrity of the mitochondrial membrane is followed by release of cytochrome C into the cytosol, this in turn leads to activation of caspase cleavage.Antiapoptotic genes Bcl-2 and proapoptotic genes Bax regulate release of cytochrome C.Bax has been shown to contain p53-binding sites in its promoter site and is upregulated in response to DNA damage and increased p53 (11). p53-mediated cell death can be inhibited by Bcl-2/Bcl-x.
2)Reactive oxygen species (ROS) are powerful activators of mitochondrial damage and apoptosis. A number of genes that increase production of ROS and therefore oxidative stress have been found to be induced by p53; these are p53-induced genes or PIGs .
3) Fas (CD95) when activated by FasL trimerizes resulting in caspase activation. Over expression of Fas can cause apoptosis and is thought to be p53 dependent, although the mechanism is not yet clear (14). p53 may upregulate Fas and induce Fas mediated death
Role of apoptosis
In each of these diverse areas implicates immense potential manipulation of apoptosis to treat disease. Research is already underway to harness apoptosis as a therapeutic tool in modern medicine. Possibilities include:
> Control of malignant disease
> Delay of premature senescence in neurodegenerative disease
> Regulation of inflammatory disease
> Treatment of autoimmune disorders
> Minimizing the area of infarct in ischemic disease, e.g. stroke, MI.
Suggested therapies on combination and improvement of p53 therapy
- use of chemotherapeutic drug in combination eg , herceptin , gleevac , tamifloxin arimedex , examstrane ,trastuzumab ,Taxane based regimens ,anthracylins ,COX inhibitors, estrogen receptor stimulators etc
-cisplatin based chemotherapy
-Avoidance of estrogen foodstuff – eg. soy
-Consumption of more alkaline foodstuff – as cancer survives and multiplies in acidic environment.
-Use of herbal medicine like – tulsi [osmium sanctum], Granoda lucidum has been a revolutionary fungal mushroom having high anti neoplastic activity .
-use of antioxidant vitamins A .D .E etc as cancer needs oxygen for its survival .
-Use of stem therapy is also tried on experimental basis .
- Monoclonal antibody therapy.
-Human pappillavirus vaccines.
Vectors enhance the p53 cancer gene therapy
Viral vectors – lentivirus, adenovirus ONYX -015, herpes ,retrovirus act as a carrier of p53 gene in cancer tumor which undergo apoptosis .
Non viral vectors –gene gun , lipofaction nakedplasmids , RNA , c ationic liposome peptide DNA complex are carrier of this gene therapy .
now the use of virus with combination of liposomes complex is used on animal xenograft models .
Conclusion
As chemotherapy show disadvantage of regrowth of cell , metastasis after surgery treatment , chemoresistance to tumor, gene therapy has been a revolutionary step towards cancer treatment . Genetic correction strategies are presently being developed and tested in animal models for human malignancies and in early patient trials. The cancer susceptibility genes p53 have been tested in ovarian & breast cancer patients, , and have shown some potential for this antitumor strategy. P53 gene therapy may be effective even against tumors that lack p53 mutations, because p53 may function as a growth inhibitor in a variety of gene transfer settings.
Key problems at present include the degradation of vector by the immune system and a need for higher levels of gene transduction. Solutions will require the development of improved vectors, improved vector delivery systems, and the fine-tuning of human gene therapy in appropriate models of human cancer.
Bibliography
1. Roth JA, Cristiano RJ: Gene therapy for cancer: what have we done and where are we going? J Natl Cancer Inst 1997, 89:21-39. [PubMed Abstract] [Publisher Full Text]
2. Malkin D, Li FP, Strong LC, et al.: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.Science 1990, 250:1233-1238
3. Harris CC: The p53 tumor suppressor gene as a target for new anticancer therapies.Adv Oncol 1998, 14:3-7.
4. p53 and breast cancer, an update.. M. Lacroix, R.-A. Toillon, and G. Leclercq (2006)Endocr. Relat. Cancer 13, 293-325
5. Apoptosis. Its significance in cancer and cancer therapy. Kerr JF, Winterford CM, Harmon BV.Department of Pathology, University of Queensland Medical School, Herston, Australia
6. Apoptosis, p53, and Tumor Cell Sensitivity to Anticancer Agents1 J. Martin Brown2 and Bradly G. Wouters Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94
About Authors
.jpg "Mr. Satish A. Polshettiwar")
Mr. Satish A. Polshettiwar
Working as Lecturer at MAEER’s, Maharashtra Institute of Pharmacy, MIT Campus, Pune. He has done his M.Pharm in Quality Assurance from Nagpur University. He has also done Diploma in IT from C-DAC. He is a Life member of like APTI and other Professional bodies. He has Published and Presented several Research articles and Review article in National level and International level.
E. Mail: contact_psatish@yahoo.co.in, Cell No. 09422842838
Mr. C.G. Deshpande
Final Year B.Pharm student at P. Dr. V.V. P’fs College of Pharmacy, Viladghat, Ahemednagar.
Mr.Anand M. Kudal*
Working as Lecturer at MAEER’s,Maharastra Institute of Pharmacy, MIT Campus, Pune. He has completed M.Pharm in Medicinal and Pharmaceutical Chemistry from Department of Pharmacy, SGSITS,Indore, RGPV, Bhopal.,
Email:anand_kudal@yahoo.com, Cell-09923090682 .
Dr. S. R. Parakh
Working as Principal and Professor in Pharmaceutics at MAEER’s, Maharastra Institute of Pharmacy, MIT Campus, Pune-411038
Email:srparakh@yahoo.com
Prof. Manish S. Wani
Working as Lecturer at MAEER’s Maharashtra Institute of Pharmacy, MIT campus, Pune. He has done his M.Pharm in Pharmaceutics from Pune University. He has also done his MBA from Pune University.