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Gene Therapy And Cancer Treatment
#1
Altering the genes as a treatment against a disease is known as gene therapy. A variety of diseases has been known to be caused as a result of defective genes in humans such as Parkinson’s disease, cystic fibrosis, haemophilia, cancer etc. Thus a change in the genes can be used as a treatment mechanism for treating the diseases.

Several modes of mechanism are followed in gene therapy:
(i) Replacement: In this therapy, the defective gene is replaced with a properly functioning one. In certain cases the diseases may be caused by loss of certain genes as a result of mutation, or the diseased condition can arise due to the genes being permanently turned off.

(ii) Regulation: Certain regulations or alterations in genes leading to decline of certain important functions or activation of some defective function can be the cause of the disease. Appropriate regulations of gene expression can lead to proper gene expression and treatment of the disease.

(iii) Enhancement of defective cell appearance: Certain disease can be caused as a result of the defective cell being not recognised by the immune system. The gene therapy is targeted so that these cells become distinct and the same is recognised by the immune system and acted upon them.

In gene therapy, a gene cannot be inserted directly into a human cell. It needs specific carriers which are known as ‘vectors’ which carry these genes into the cell. In gene therapy, viruses are mainly used as vectors.

Depending on the target cell, the gene therapy can be divided into two main types:-
Germline gene therapy and Somatic cell gene therapy.

In germline gene therapy, the gene transfer is targeted to germ cells and the modification of genes in the same is acquired. This results in transfer of modified genes into the future generations. This can help in eradicating certain diseases from a family or from a population as a whole. But this process has been so far possible only theoretically. The dangerous implications of the proposed methodology have inhibited it from being acquiring acceptance.

In somatic gene therapy, the gene is introduced into somatic cells of the diseased. The gene is introduced into the somatic cells where the expression of critical genes is important for restoration of specific cellular activity. Since somatic cells are non reproductive this change in the genes are not transferred into the next generations and remain in the same species.

Mode of action:
In gene therapy, mostly a normal gene is replaced in the position of a defective gene. This transfer of corrected gene is done with the help of carriers known as vectors. The most common vector used in these cases is viruses which have been genetically altered so that it does not actually affect the person negatively but rather improves the diseased condition of the person. The vectors are directed to infect target cells that are cells where a defective gene is present and the corrected genetic material is unloaded into the defective cell. The correction of the defects helps in restoration of the defective condition.

Cancer treatment by gene therapy:-
Gene therapy has been applied most successfully in the treatment of cancer. The property of selective targeting and tumour destruction is the most prominent accounting to its use in cancer cure. A main example is defective P53 gene in tumour cell. The P53 gene is a tumour suppressor gene. It is seen that in persons with tumour, the P53 gene has been affected with mutations and is non functional. Introduction of wild type gene by gene therapy into the affected persons restores the functional gene and results in death of tumour cells.

Another major example in gene therapy in cancer cure is regulation of K-RAS. This is an oncogene known for causing cancer. In cancerous condition, the over expression of the corresponding gene is reported. Gene therapy facilitates introducing antisense gene into the cell over expressing this gene. This causes silencing of the corresponding gene by formation of double stranded RNA affecting the protein production and expression.

The process also involves several risk factors the main one being instability of viruses. The viruses which are used as vectors may develop its infectious property and lead to toxicity, immune responses from the body or the accidental integration into some other site will lead to lethal conditions.
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#2
Potentials of cancer gene therapy

Genes define all aspects of our life and determine all characteristic that we posses: color of our eyes, height, favorite food and music and susceptibility to various disorders. With over 200 different cancer types and increasing number of sick people all over the globe - cancer is the plague of 21st century. A lot of treatments were discovered so far, but we still don't have perfect tool against cancer. Gene therapy appeared recently and already showed promising effects in the treatment of malignant disorders, but a lot of work still had to be done before we can be sure that mankind won a battle against the cancer.

Early recognition is usually the best chance for patients to survive the cancer. Unfortunately, some types can’t be recognized until disease is in advanced stage, when nothing can be done. Ovarian cancer is typical example of a cancer that doesn’t show any clinical manifestation in the early stage of disease, and when it is diagnosed - effective therapeutic solution doesn't exist. Extensive research in this area identified gene responsible for ovarian cancer. Experiments focused on gene silencing showed that this technique can be perfect solution in treatment of ovarian cancer.

HMGA2 protein belongs to the high mobility group of nuclear nonhistone phosphoproteins. Since HMGA2 is one of chromosomal proteins, it is included in chromatin organization, control of the cell cycle, interaction with transcriptional factors and cellular senescence. HMGAs gene is active during embryonic development. Completed cell differentiation is signal for gene regulators to silence HMGA2. Expression of this gene in adults is associated with myeloproliferative disorder, retinoblastoma, breast, ovarian and non-small lung cancer. Most probably, malfunction of regulatory factors, which keep HMGA2 silenced, result in activation of the gene expression. This gene is not associated with any cellular function in adult, differentiated cell, and thus it is ideal candidate for gene silencing. Series of experiments using ovarian cancer cell lines showed that gene silencing result in cell growth arrest, by keeping the cells in the G1 phase (which precedes mitosis). Experiments continued in vivo on mice. Injection of antisense HMGA2 fragments showed excellent results. All animals survived the treatment and HNGA2 silencing resulted in shrinkage or even disappearance of the cancer tissue (depending on a dose and duration of the treatment). Ideal gene candidate for gene silencing must not be implicated in important cellular processes because silencing would disturb not just cancer proliferation but some other vital process that would be equally harmful for the healthy tissue. This experiment and identified gene represent an example of ideal gene candidate for cancer therapy. After final evaluation in lab animals, it can become part of regular ovarian cancer treatments in humans.

Genetic profile of cancer patients can be useful predictor of effectiveness in a standard drug treatment. International Genome Consortium is alliance of laboratories that collect list of mutations associated with various cancer types. This base already contains genetic profiles of 3000 breast cancers samples (among others cancer types); main goal is to improve treatment options by choosing the most effective therapy. Different drugs are used in cancer treatment, but patients show unequal response even though they have the same disease. Group of women with estrogen receptor positive breast cancer were genotyped and list of mutated genes were identified. Healthy women served as “control”, to help distinguish modified from normal genes. Mutations in genes p53 (cancer suppressor), MAP3K1 and MAP2K4 (cell growth promoters) were expected, but five genes associated with leukemia came as a surprise. When clinical data was compared with altered genes, it was shown that women with mutated p53 genes don’t respond equally well as women that have normal version of the gene. Also, women with mutation in MAP3K1 and MAP2K4 showed better response to the currently applied drug than women that carry normal version of these genes. This experiment showed that genotyping (that is not as expensive as it was before), can be useful tool prior choosing appropriate cancer therapy.

Gene therapy has massive potential and numerous applications in medicine. Cancer could be treated through gene silencing or by choosing ideal (most effective) drug treatment. Common factor in both methods is selection of ideal gene candidate. That is usually the hardest part in gene targeted cancer therapy.
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