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Gene Therapy And Cancer

Discussion in 'Oncology' started by waleed, Oct 6, 2011.

  1. waleed

    waleed Moderator

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    some definitions ....>>

    _(genes)=A gene is a unit of heredity in a living organism.

    _(the genetic code)= it's the arrangement of a particular sequence of nucleotide in the DNA which is transcribed to a complementary sequence in mRNA which goes to ribosomes where it's translated into a particular sequence of amino acids in a polypeptide which makes a particular protien

    _(DNA replication)=dna is replicated so that each new cell recieves a complete copy of original cell's GENETIC INFORMATION.


    _(mutation)...=mutations are changes in a genomic sequence.. the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus.N.B..these can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely.

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    TYPES OF gene therapy...??

    1-germ like gene therapy and
    2-somatic gene therapy
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    CANCER....GENOME.....>
    The Cancer Gene( Census) is an ongoing effort to catalogue those genes for which mutations have been causally implicated in cancer
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    Patients whose tumors had mutations in three commonly mutated genes lived longer than patients without these mutations, the researchers found. In addition, some patients had mutations in genes that encode proteins in the mTOR pathway''i.e''( A protein that helps control several cell functions, including cell division and survival, and binds to rapamycin and other drugs. mTOR may be more active in some types of cancer cells than it is in normal cells. Blocking mTOR may cause the cancer cells to die. It is a type of serine/threonine protein kinase. Also called mammalian target of rapamycin.)......
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    To gain insights into the genetic basis of the tumor, the researchers sequenced nearly all of the protein-coding genes in tumor and normal tissue samples from 10 patients with pancreatic neuroendocrine tumors. (((The patients did not have an inherited form of the disease.))))
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    The three most commonly mutated genes in the 10 tumors—MEN-1, DAXX, and ATRX—all play a role in the packaging of DNA. Known as chromatin remodeling, this is an epigenetic process that controls the activity of genes without causing changes in DNA sequence
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    N,B ........>>Patients with mutations in MEN1 or DAXX/ATRX tended to live longer than patients without the mutations. The difference was particularly striking among patients who had metastatic disease and whose tumors had mutations in both MEN1 and DAXX/ATRX. These patients all survived at least 10 years, whereas more than 60 percent of the patients without the mutations died within 5 years of diagnosis.becuz...this patient with mutations in MEN1 and DAXX/ATRX may have a biologically distinct subtype of pancreatic cancer.
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    VVVV.IMP......>>Multiple endocrine neoplasia type 1 (MEN1), among all syndromes, causes tumors in the highest number of tissue types. Most of the tumors are hormone producing (e.g., parathyroid, enteropancreatic endocrine, anterior pituitary) but some are not (e.g., angiofibroma). MEN1 tumors are multiple for organ type, for regions of a discontinuous organ, and for subregions of a continuous organ. Cancer contributes to late mortality; there is no effective prevention or cure for MEN1 cancers. Morbidities are more frequent from benign than malignant tumor, and both are indicators for screening. Onset age is usually earlier in a tumor type of MEN1 than of nonhereditary cases. Broad trends contrast with those in nonneoplastic excess of hormones (e.g., persistent hyperinsulinemic hypoglycemia of infancy). Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin. Similarly, 11q13 loss of heterozygosity in tumors predicts inactivation of the other MEN1 copy. MEN1 somatic mutation is prevalent in nonhereditary, MEN1-like tumor types. Compiled germline and somatic mutations show almost no genotype/phenotype relation. Normal menin is 67 kDa, widespread, and mainly nuclear.
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    N.B.....Multiple endocrine neoplasia type 1 (MEN 1) is a relatively uncommon inherited disease. Individuals who inherit the gene for MEN 1 have an increased chance of developing over-activity and enlargement of certain endocrine glands. The endocrine glands most commonly affected by MEN 1 are the parathyroid glands, the pancreas, and the pituitary glands.IT'S VERY rare .......What Age Does MEN 1 Usually Present Itself?..ANSWER IS ...>By age 30, most people who inherit MEN 1 will have some type of endocrine gland over-activity. Over-activity from the adenoma can usually be detected by special blood tests (measurement of ionized calcium and parathyroid hormone in the blood) before people reach age 30. Symptoms, however, do not develop in many people with MEN 1 until they are older than 30. For this reason it is important for all people at risk to be tested for MEN 1, even though they may feel quite well.Most of the endocrine problems related to MEN 1 are not cancerous (malignant).
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    N.B......ATRX syndrome

    ATRX syndrome is characterized by X-linked mental retardation associated with α-thalassemia. The gene mutated in this disease, ATRX, encodes a plant homeodomain-like finger and a SWI2/SNF2-like ATPase motif, both of which are often found in chromatin-remodeling enzymes, but ATRX has not been characterized biochemically. By immunoprecipitation from HeLa extract, we found that ATRX is in a complex with transcription cofactor Daxx. The following evidence supports that ATRX and Daxx are components of an ATP-dependent chromatin-remodeling complex: (i) Daxx and ATRX can be coimmunoisolated by antibodies specific for each protein; (ii) a proportion of Daxx cofractionates with ATRX as a complex of 1 MDa by gel-filtration analysis; (iii) in extract from cells of a patient with ATRX syndrome, the level of the Daxx”“ATRX complex is correspondingly reduced; (iv) a proportion of ATRX and Daxx colocalize in promyelocytic leukemia nuclear bodies, with which Daxx had previously been located; and (v) the ATRX complex displays ATP-dependent activities that resemble those of other chromatin-remodeling complexes, including triple-helix DNA displacement and alteration of mononucleosome disruption patterns. But unlike the previously described SWI/SNF or NURD complexes, the ATRX complex does not randomize DNA phasing of the mononucleosomes, suggesting that it may remodel chromatin differently. Taken together, the results suggest that ATRX functions in conjunction with Daxx in a novel chromatin-remodeling complex. The defects in ATRX syndrome may result from inappropriate expression of genes controlled by this complex.
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    ''CANCER TREATMENT BY GENE THERAPY''
    Autologous lymphocytes -- a person's own white blood cells -- have previously been used to treat metastatic melanoma. In a process called adoptive cell transfer, lymphocytes are first removed from patients with advanced melanoma. Next, the most aggressive tumor-killing cells are isolated, multiplied in the lab, and then reintroduced to patients who have been depleted of all remaining lymphocytes. While reasonably successful, this method can only be used for melanoma patients and only for those who already have a population of specialized lymphocytes that recognize tumors as abnormal cells.
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    Thus, NCI researchers, led by Steven A. Rosenberg, M.D., Ph.D., sought an effective way to convert normal lymphocytes in the lab into cancer-fighting cells. To do this, they drew a small sample of blood that contained normal lymphocytes from individual patients and infected the cells with a retrovirus in the laboratory. The retrovirus acts like a carrier pigeon to deliver genes that encode specific proteins, called T cell receptors (TCRs), into cells. When the genes are turned on, TCRs are made and these receptor proteins decorate the outer surface of the lymphocytes. The TCRs act as homing devices in that they recognize and bind to certain molecules found on the surface of tumor cells. The TCRs then activate the lymphocytes to destroy the cancer cells.

    In this study, newly engineered lymphocytes were infused into 17 patients with advanced metastatic melanoma. There were three groups of patients in this study. The first group consisted of three patients who showed no delay in the progression of their disease. As the study evolved, the researchers improved the treatment of lymphocytes in the lab so that the cells could be administered in their most active growth phase. In the remaining two groups, patients received the improved treatments. Two patients experienced cancer regression, had sustained high levels of genetically altered lymphocytes, and remained disease-free over one year. One month after receiving gene therapy, all patients in the last two groups still had 9 percent to 56 percent of their TCR-expressing lymphocytes. There were no toxic side effects attributed to the genetically modified cells in any patient.

    Approaches to increase the function of the engineered TCRs -- including the development of TCRs that can bind to tumor cells more tightly -- and to further optimize delivery methods using retroviruses are under investigation. In addition, the researchers believe it may be beneficial to further modify lymphocytes by inserting molecules that assist in directing lymphocytes to cancerous tissues. Clinical trials are being conducted to enhance treatment effectiveness using total body radiation therapy to deplete a patient's supply of non-altered lymphocytes before replacing them with purely engineered cells. The researchers also have isolated TCRs that recognize common cancers other than melanoma.

    "We are currently treating advanced melanoma patients using adoptive transfer of genetically altered lymphocytes, and we have now expressed other lymphocyte receptors that recognize breast, lung, and other cancers," said Rosenberg.

    "These very exciting successes in treating advanced melanoma bring hope that this type of gene therapy, altering lymphocytes, could be used in many types of common cancers and could be achievable in the near future," said Acting NCI Director John E. Niederhuber, M.D. He acknowledged Rosenberg for his persistent and visionary study of the role of the immune system in the treatment of cancer. "He is one of the leaders we all look to for moving us forward," Niederhuber said.

    Skin cancer is the most common of all cancers. According to the American Cancer Society, melanoma accounts for about 4 percent of skin cancer cases, but it is also the most serious and most aggressive type. In the United States, an estimated 62,190 new cases of melanoma will be diagnosed and approximately 7,910 people will die of the disease in 2006.
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    >...BREAST CANCER GENES ....

    _BRCA-1,BRCA-2,P53,ATM,P65

    1_BRCA-1........named Breast Cancer 1 (BRCA-1), was finally isolated in Chromosome #17, one of the 23 pairs of chromosomes found in most human cells. An altered BRCA-1 has been linked to the development of breast and ovarian cancer.However preliminary studies have shown that testing positive for an altered BRCA-1 gene does not necessarily mean a woman will develop breast cancer. If a woman tests negative (that is, she does not have the altered gene), this does not necessarily mean she will be free of breast cancer during her lifetime.


    2_BRCA-2.........located the gene BRCA-2 on Chromosome #13. Like BRCA-1, BRCA-2 appears to be a cancer-causing gene when altered. BRCA-2 appears to account for as many cases of breast cancer as does BRCA-1. BRCA-2 apparently triggers breast cancer in males as well as in females.

    3_P53........../(protein that in humans is encoded by the TP53 gene)...There are specific genes in the cells of our bodies that normally help to prevent tumors from forming. One of these tumor-suppressor genes , called P53 ("p" for protein and "53" for its weight) was recently named "Molecule of the Year" by the editors of the journal Science . This protein plays a major role in cell growth. The job of P53 is to prevent (suppress) cells from growing. When it has been damaged or altered, P53 loses its ability to block cell growth. Changes to the gene result in an increased risk of cancer. Almost 50% of all human cancer cells contain a P53 mutation. These cancers are more aggressive and more often fatal. Since P53 is so important for normal cell growth in humans, researchers are continuing to look for ways to diagnose, prevent, and treat cancer associated with P53.


    4_ATM.........After more than a decade of intensive searching, researchers have isolated a recessive gene that increases the risk for people to develop some kinds of cancer (as well as a rare genetic disease). The gene, ataxia telangiectasia mutated (ATM) may be involved in many cancers, including breast cancer. The normal role of the ATM gene is to control cell division. Although researchers do not know why an altered ATM causes cancer, 1% of Americans (more than 2 million people) carry at least one copy of the defective form of the gene. By examining the role of altered ATM genes, scientists are hoping to shed some light on what makes cells live, grow, and die.

    Besides being associated with cancers, the ATM gene may also identify those individuals who are sensitive to radiation. The altered form of the ATM gene is closely linked to a childhood disorder of the nervous system called Ataxia Telangiectasia, or AT. AT afflicts 1 in 40,000 children in the U.S. and 1 in 200,000 worldwide each year.


    5_P65.......With the recent discovery of the gene called P65, scientists are hoping to develop a blood test to detect cancers of the breast and prostate at a much earlier stage than is now possible. The altered form of P65 is linked to the overproduction of certain hormones that may help to cause both breast and prostate cancers. The new blood test, called the tumor blood marker , hopefully will allow doctors to monitor a patient's response to cancer treatment. The level of the P65 protein marker in the blood decreases as tumors are destroyed during therapy. A study is being performed to determine if the tumor marker blood test is suitable for widespread use.
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    ..(N.B)NUMBER 3.....P53..... humans, p53 is encoded by the TP53 gene located on the short arm of chromosome 17
    For these mammals, the gene is located on different chromosomes:

    * Chimp and orangutan, chromosome 17
    * Macaque, chromosome 16
    * Mouse, chromosome 11
    * Rat, chromosome 10
    * Dog, chromosome 5
    * Cow, chromosome 19
    * Pig, chromosome 12
    * Horse, chromosome 11
    * Opossum, chromosome 2


    FUNCTIONS OF P65 .....>P53 has many anticancer mechanisms, and plays a role in apoptosis, genetic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms:

    * It can activate DNA repair proteins when DNA has sustained damage.
    * It can induce growth arrest by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle).
    * It can initiate apoptosis, the programmed cell death, if DNA damage proves to be irreparable.

    p53 pathway: In a normal cell p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.

    Activated p53 binds DNA and activates expression of several genes including WAF1/CIP1 encoding for p21. p21 (WAF1) binds to the G1-S/CDK (CDK2) and S/CDK complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity.

    When p21(WAF1) is complexed with CDK2 the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division. Thus, cells will divide uncontrollably, and form tumors.

    Recent news :
    NEW YORK, NY--(Marketwire - February 4, 2011) - Scientists have discovered a protein that prevents prostate cancer cells from growing. The protein even makes the cells "kill themselves." Researchers at Imperial College London said the discovery could help doctors tell the difference between common, slow growing forms of prostate cancer from the aggressive, faster growing forms. However, Dr. David B. Samadi, a robotic prostatectomy, robotic surgery, and prostate cancer treatment expert, Vice Chairman, Department of Urology, and Chief of Robotics and Minimally Invasive Surgery at The Mount Sinai Medical Center said, "This is an exciting discovery for the field and gives us hope that one day we can manage and prevent prostate cancer."
    Researchers found the protein, FUS, which occurs naturally in cells, may curb the growth of prostate cancer cells and begin a chain of events that leads to their death, according to a report in the journal Cancer Research. When the amount of FUS was increased, more cells died, which suggested that a drug that boosts the protein levels in patients could prove beneficial in preventing prostate cancer cells from spreading beyond the prostate gland.
    The FUS protein is also linked to the severity of prostate cancer, which tends to be more severe in men with lower levels of the protein. Researchers say that FUS could be crucial in the progression of prostate cancer. However, it is still not clear if FUS could be useful in determining how aggressive prostate cancer is. Increasing FUS levels could possibly slow down prostate cancer tumor growth or improve response to hormone therapy.
    However, it should be noted that FUS only slows the growth of prostate cancer cells when grown in controlled conditions. Dr. Samadi believes that merely prostate cancer cells act differently in a lab versus than in the human body, which may not represent a true picture of how the protein will behave in reality. "It is important to remember that more research will be needed on this discovery, so it will still be some time before men who are diagnosed with prostate cancer will see direct benefits," said Samadi.
    Critics say many prostate cancer patients undergo unnecessary surgeries and therapies, which often carry a high risk of incontinence and impotence. Not so, says Dr. Samadi, who developed the robotic prostate surgery method known as the SMART Surgery Technique. "SMART Surgery removes prostate cancer with improved sexual function and continence recovery," said Samadi, a robotic prostate surgery expert with over 3,200 successful surgeries to his credit."Currently, doctors use a variety of prostate cancer screening methods, including blood tests and biopsies, to determine who is most at risk and how they should be treated," said Dr. Samadi, "but science has yet to give us a single tool that is completely reliable." The FUS research is still in its early stages, but if further studies confirm the findings, FUS could hold promise for future therapies.
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    Source :Medical Inspiration-For doctors and Medical students: Gene Therapy And Cancer
     

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