cancergenesandgrowthfactors-100301173509-phpapp01

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Cancer Genes


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What is cancer? The phenomenon of cancer can be

defined on various levels. On the

most basic level, cancer representsthe collapse of the cooperation

between the ten million cells of

human being . This results in the

selfish, uncontrolled growth of cellswithin the body which eventually

leads to the death of the organism.


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History of Cancer:- Cancer as described by the ancientEgyptians (3000 BC to 1500 BC):- The oldest known description of humancancer is found in an Egyptian sevenpapyri or writing written between 3000-1500 BC. Two of them, known as the"Edwin Smith" and "George Ebers" papyri. The Edwin Smith Papyrus describes eight

cases of tumors or ulcers of the breast.


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The document acknowledged that there is no

treatment for this condition and recommended

cauterization as a palliative measure.

The ancient Egyptian medicine mixed

medicine and religion.

Hieroglyphic inscriptions suggest that ancient

physicians were able to distinguish between

benign and malignant tumors.


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Origin of the word carcinoma:- Hippocrates, the great Greek physician consideredthe father of medicine, is though to be the first

person to clearly recognize difference betweenbenign and malignant tumors.

Hippocrates noticed that blood vessels around amalignant tumor looked like the claws of crab. He

named the disease karkinos(the Greek name forcrab)

In English, this term translates to carcinos orcarcinoma.


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Later in the course of history, the causeof cancer was explained as the result of

an excess of black bile. Autopsies, performed by Harvey in the

17th century, gave an insight in to the

circulation system. By about the sameperiod Gaspare Aselli discovered thelymphatic system

New theory suggested that abnormalitiesin the lymph and lymphatic system as theprimary cause of cancer.


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Discovery ofanesthesia in 1844 by Wells allowed

surgery to flourish and the classic cancer

operations such as radical mastectomy were

developed.

The discovery ofmicroscope by Leeuwenhoek in

the late 17th century added momentum to the quest

for the cause of cancer.

By late19th century, with the development ofbetter

microscopes to study cancer tissues.

These studies showed that cancer cells are markedly

different in appearance compared to the

surrounding normal cells


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Rudolf Virchow, who is often called thefounder ofcellular pathology, provided the

scientific basis for the modern pathologicstudy of cancer and correlated the clinical

course of illness with microscopic findings.

This approach led to the development ofmodern cancer surgery


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** Cancer is a geneticdisorder:- Four lines of evidence converged to

demonstrate that cancer is a geneticdisease:-

1- Chromosomal anomalies incancer:-in chronic myelogenous leukemia (CML)

translocation between chromosome 9 &chromosome 22 forming Philadelphiachromosome


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2- Families in which cancer is transmitted as agenetic trait e.g. Li-Fraumeni Syndrome,inherited asautosomal dominant trait.

3- Overlap between carcinogens &mutagens.

4- Individuals with DNA repair deficiencysyndromeare at increased risk of cancer e.gXeroderma pigmentosum, inability to repairDNA damage done by U.V exposure leads tohigh incidence of cancer skin.


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What Are Mutations? Mutations are changes in the arrangement of

the bases that make up a gene.

A mutated (altered or changed) gene may tellthe cell to make an abnormal protein, which nolonger functions properly

This may not have any effect at all, or it maylead to a disease.

Some diseases like sickle cell anemia arecaused by gene mutations


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Types of mutations:-

1-Hereditary mutations:-are gene changes (mutations) that come from a

parent and therefore exist in all cells of the body,including reproductive cells.

passed from generation to generation

These are also called germline mutations. Thistype of mutation is a major factor for 5% to 10% ofcancers.


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2- Acquired mutations:- occurs when DNA in a cell changes during the

persons life.

caused by environmental influences suchas exposure to radiation or toxins.

they are not in the reproductive cells.

They are not in every cell of the body like thehereditary mutations but only in the tumor orcancer cells. called sporadic or somatic

mutations.


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mutations in our cells happen all the time

our genes can recognize and repair theabnormality

If it cant be repaired, the cell will actually

begin a process called apoptosisthat leads toits death.

If the mutation occurs in a gene that helpscontrol how often a cell divides or one thatchecks for errors in cell division, it may

contribute to a person developing cancer.

cancer may also occur because the mutationhappens in a gene that normally causes a

defective cell to die.


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Most scientists today believe that cancer develops in

a process that involves more than one mutations

person may inherit a form of one or more genes thatmakes him or more likely to develop a specific type

of cancer.

On top of this, he may acquire other mutationsbecause of exposure to cigarette smoke, excess

sunlight, or viruses.

Therefore, some people may be more likely todevelop cancer than others simply because they

were born with mutations in their genes.


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Gene Mutations That Can Lead to

Cancer:-

The 2 maintypes of genes that are now recognizedas playing a role in cancer are oncogenesand

tumor suppressor genes.**What Are Oncogenes?-Oncogenesare mutated forms of genes that

cause normal cells to grow out of control and

become cancer cells.

- They are mutations of certain normal genes of thecell called proto-oncogenes.


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Proto-oncogenes are the genes that normally

control how a cell divides and the degree to which

it differentiates

When a proto-oncogene mutates into an

oncogene, it becomes permanently "turned on" oractivated

When this occurs, the cell divides too quickly,which can lead to cancer


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think of a cell as a car:-A proto-oncogene normally functions in away that is similar to a gas pedalAn oncogene could be compared to a gas

pedal that is stuck down, cell to divide outof control


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Pathway of normal cell

growth:-

starts with growth factor, which locks ontoa growth factor receptor.

The signal from the receptor is sent througha signal transducer.

A transcription factoris produced, whichcauses the cell to begin dividing.

More than 100 oncogenes are nowrecognized Scientists have dividedoncogenes into the 5 different classes


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1-Growth factors These oncogenes produce factors that

stimulate cells to grow.

The best known of these is called sis

It leads to the overproduction of a proteincalled platelet-derived growth factor (PDGF),which stimulates cells to grow.

Vascular endothelial growth factor (VEGF) &Fibroblast growth factor (FGF) are othergrowth factors.


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2- Growth factor receptors Normally turned "on" or "off" by growth factors. When

they are "on," they stimulate the cell to grow. Theymay become always in the on state in 2 cases:-

a- Certain mutationsin the genes that produce

them. b- gene amplification:

This means that instead of the usual 2 copies of thegene, there may be several extras, resulting in toomany growth factor receptor molecules.

The best-known examples of growth factor receptorgene amplification are erb Band erb B-2.


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3- Signal transducers These are the intermediate pathways between the

growth factor receptor and the cell nucleus wherethe signal is received.

Like growth factor receptors, these can be turned

on or off. When they are abnormal in cancer cells,they are turned on

Two well-known signal transducers are abl and ras.

Abl is activated in chronic myelocytic leukemia andis the target of the most successful drug for thisdisease, imatinib or Gleevec. Abnormalities of rasare found in many cancers.


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4- Transcription factors These are the final molecules in the chain that tell

the cell to divide.

These molecules act on the DNA and control whichgenes are active in producing RNA and protein.

The best known of these is called myc. In lungcancer, leukemia, lymphoma, and a number ofother cancer types, myc is often overly activated

and stimulates cell division.


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5- Programmed cell death

regulators:

These molecules prevent a cell from committingsuicide when it becomes abnormal

When these genes are overactive, they preventthe cell from going through the suicide process.This leads to an overgrowth of abnormal cells,which can then become cancerous.

The most well described one is called bcl-2. It isoften activated in lymphoma cells.


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Tumor suppressor genes


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What Are Tumor Suppressor Genes?

are normal genes that slow down cell division,repair DNA mistakes, and tell cells when to die(apoptosis or programmed cell death).

When tumor suppressor genes dont work properly,cells can grow out of control, which can lead tocancer.

About 30 tumor suppressor genes have been

identified, including p53, BRCA1, BRCA2, APC,and RB1.

A tumor suppressor gene is like the brake pedal ona car


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An important difference between oncogenes andtumor suppressor genes is that oncogenes result

from the activation(turning on) of proto-oncogenes,but tumor suppressor genes cause cancer when theyare inactivated(turned off).

Another major difference is that while theoverwhelming majority of oncogenes develop frommutations in normal genes (proto-oncogenes) duringthe life of the individual (acquiredmutations),

abnormalities of tumor suppressor genes can beinherited as well as acquired.


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Types of Tumor Suppressor Genes

1- Genes that control cell division :-

TheRB1 (retinoblastoma) gene is an example of such a gene.

Abnormalities of the RB1 gene can lead to (retinoblastoma)

in infantsthere are always 2 copies of each gene. But the inherited

RB1 mutation only affects one of the gene pairs

during the infants development, a random mutation can

occur in the normal copy of the RB1 gene. Scientists callthis process loss of heterozygosity (LOH)


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2- Genes that repair DNA

when a cell prepares to divide into 2 new cells, itmust duplicate its DNA. copying errors sometimes

occur but cells haveDNA repair genes, whichmake proteins that proofread DNA

The genes responsible for HNPCC (hereditarynonpolyposis colon cancer) are examples of DNArepair gene defects. When these genes do not repair

the errors in DNA, HNPCC can result. HNPCCaccounts for up to 5% of all colon cancers andsome endometrial cancers.


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3- Cell "suicide" genes :-

If there is too much damage to a cells DNAcouldn't be repaired by DNA repair system

Cell is directed to be destroyed what is called(programmed cell deathor apoptosis)

the p53tumor suppressor gene is responsiblefor this apoptosis

If thep53gene is not working properly, cells with

DNA damage that has not been repairedcontinue to grow and can eventually become

cancerous


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Abnormalities of the p53 gene are sometimesinherited, such as in theLi-Fraumeni

syndrome (LFS). People with LFS have a higher risk for

developing a number of cancers, includingsoft-tissue and bone sarcomas, brain tumors,breast cancer, adrenal gland cancer, andleukemia.

Many sporadic (not inherited) cancers such as

lung cancers, colon cancers, breast cancersas well as others often have mutated p53 geneswithin the tumor.


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Inherited Abnormalities of TumorSuppressor Genes

In addition to mutations in p53, RB1, and thegenes involved in HNPCC, several othermutations in tumor suppressor genes can be

inherited. A defectiveAPCgene causesfamilial

polyposis, a condition in which people develophundreds or thousands of colon polyps

Abnormalities of theBRCA genes account for5% to 10% ofbreast cancers.


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Non-inherited mutations of tumor

suppressor genes

Mutations of tumor suppressor genes have beenfound in many cancers.

abnormalities of the p53 gene have been found inover 50% of human cancers.

Acquired mutations of the p53 gene appear to beinvolved in a wide range of cancers, including lung,colorectal, and breast cancer

acquired changes in many other tumor suppressorgenes also contribute to the development of sporadic(not inherited) cancers.


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Other non-inherited

cancers seen with this

geneAbnormal geneInherited cancer

Many different cancersRBIRetinoblastoma

Many different cancersP53Li-Fraumeni Syndrome (sarcomas,

brain tumors, leukemia)

Many different cancersINK4aMelanoma

Most colorectal cancersAPCColorectal cancer (due to familialpolyposis)

Colorectal, gastric, endometrial cancersMLH1, MSH2, or MSH6Colorectal cancer (without polyposis)

Only rare ovarian cancersBRCA1, BRCA2Breast and/or ovarian

Wilms tumorsWTIWilms Tumor

Small numbers of colon cancers,

melanomas, neuroblastomaNF1, NF2Nerve tumors, including brain

Certain types of kidney cancersVHLKidney cancer

H C O d T


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How Can Oncogenes and Tumor

Suppressor Genes Be Used to Help

Prevent Cancer? Several mutations in oncogenes and tumor

suppressor genes useful in helping decide

which people are at higher riskfor developingcancers.

Genetic testing can be used to look for suchmutations.

The testing is often expensive

Finding a genetic mutation can have asignificant impact on a persons life, as well as

the lives of other family members.


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How Can Oncogenes and Tumor Suppressor

Genes Be Used to Help Guide Treatment of

Cancer? specific gene changes help predict either patients have a

better or worse prognosis or which patients are likely

tobenefit

from certain treatments. women with breast cancer that contains the HER2/neu

(erbB-2) mutation tend to fare worse than women

without the mutation.

Some tests for certain gene mutations are very sensitivein finding cancer that persists or returns after treatment.

This type of test identify patients at risk of relapse, who

might benefit from additional chemotherapy.


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Related Cancersncogene/Tumor SuppressorGeneBreast and ovarian cancerBRCA1, BRCA2

Chronic myelogenous leukemiabcr-abl

B-cell lymphomabcl-2

Breast cancer, ovarian cancer, othersHER2/neu (erbB-2)

NeuroblastomaN-myc

Ewing tumorEWS

Burkitt lymphoma, othersC-myc

Brain tumors, skin cancers, lung cancer,

head and neck cancers, othersp53

Colorectal cancersMLH1, MSH2

Colorectal cancersAPC


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How Can Oncogenes and Tumor

Suppressor Genes Be Used toTreat Cancer?


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Trastuzumab (Herceptin)


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humanized monoclonal antibodies that

acts on the HER2\neu (erbB2)

receptors.

as inhibition of cell growth by

trastuzumab is limited to HER2-positive cancers, testing tumors for

HER2 expression became integral to

selecting patients HER2 testing of breast cancer patients

becomes a routine


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Mechanism of action:-


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Mechanism of action:


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How it is given ?

Herceptin is given by a drip (infusion )

The first dose is given slowly, usually over aboutan hour and a half. After this, doses normally

take about 30 minutes.The drug may be given once a week or onceevery three weeks.

If Herceptin is given together with Taxol orTaxotere, they are given in the normal way,which is usually every three weeks.


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Uses:-

Herceptin is used mainly to treat women with

breast cancer

It may be used in the early stages to increase

the chances of a cure

It also used in metastatic breast cancer

In most cases it is used in combination with

chemotherapeutic agents paclitaxel or

docetaxel


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Side effects:

1- Effects on the heart:

Herceptin may lead to cardiomyopathy or congestive

heart failure sprcially if taken with carboplatin, it

is recommended that Herceptin is not given topeople with a history of heart disease or high blood

pressure.

2- Flu-like symptoms

This includes a high temperature (fever) and chills,

shortly after the drug is given.

3 Tumour pain:


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3- Tumour pain:

Some people may experience mild pain in partsof the body to which the breast cancer hasspread.

4- Diarrhea

5- Headaches

6- Allergic reactions:

This is a rare side effect of Herceptin. Signs ofthis include skin rashes and itching,

wheezing, difficulty breathing, andbreathlessness.


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Cetuximab (Erbitux)


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a monoclonal antibody, In the UK it is currently

used to treat cancer of the colon and rectum

specially advanced or metastatic cancer.

cetuximab is given in combination with the drug

irintocan . Cetuximab is also used with

radiotherapy to treat locally advanced headand neck cancer.

Cetuximab is also being used in research trial to

treat other types of cancer, including non-smallcell lung cancer (NSCLC) and breast cancer.


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Cetuximab attaches to the EGFRs andprevents the receptors from being activated.

This stops the cells from dividing. thereforestop the cancer cells from growing.

Cetuximab also make the cancer cells moresensitive to chemotherapy and radiotherapy

Tests may be done to find the level of EGFRin the tumour cells before cetuximab is given.


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Dosage and administration:

Cetuximab is a colourless liquid

Cetuximab is given by a drip into the vein

(intravenously) through cannula. The first dose isgiven slowly, usually over two hours.

After this, doses are given weekly and this normallytakes about an hour. The first dose is usually larger

than the weekly maintenance treatments.


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Possible side effects:-

1-Allergic reactions skin rashes and itching, afeeling of swelling in the tongue or throat

antihistamines can be given

2- nausea and less commonly vomiting

3- Diarrhea This can usually be controlled with

medicine

4- Fever and chills5- dyspnea Some people may become breathless

Pertuzumab


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Pertuzumab also called 2C4, formerly known as Omnitarg is a

monoclonal antibody. The first of its class in a lineof agents called "HER dimerization inhibitors".

By binding to HER2, it inhibits the dimerization ofHER2 with other HER receptors, which ishypothesized to result in slowed tumor growth.

Early clinical trials of pertuzumab in prostate,breast, and ovarian cancers have been met withlimited success.


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Imatinib (Gleevec)


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Imatinib(Gleevec)

It i d i t ti g chronic myelogenous


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It is used in treating chronic myelogenous

leukemia (CML), gastrointestinal stromal

tumors (GISTs) and a number of othermalignancies.

It is the first member of a new class of agentsthat act by inhibiting particular tyrosine

kinase enzyme, instead of non-specifically

inhibiting rapidly dividing cells.


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Imatinib is specific for the TKdomain inabl

(the Abelson proto-oncogene), and PDGF-R

(platelet-derived growth factor receptor).

In chronic myelogenous leukemia , the

philadelphia chromosome leads to a fusion

protein ofabl with bcr(breakpoint cluster

region), termedbcr-abl. As this is now a

continuously active tyrosine kinasae, imatinibis used to decreasebcr-ablactivity.

Uses


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Uses

1- Imatinib is used inchronic myelogenous leukemia

2- gastrointestinal stromal tumors (GISTs)

3- 3- number of other malignancies as certain braintumors such as high grade gliomas includingrecurrent glioblastoma

4- Recent mouse animal studies at Emory Univerty inAtlanta have suggested that imatinib may be useful intreating Small pox

Adverse effects:


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Adverse effects:

edema, nausea, rash and musculoskeletal

pain are common but mild.

Severe congestive heart failure is an

uncommon but recognised side effect of

imatinib and mice treated with large doses of

imatinib show toxic damage to theirmyocardium.


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Gefitinib(Iressa)


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uses:

Gefitinib is used alone (monotherapy) for the

treatment of patients with a certain type of

lung cancer (non-small cell lung cancer or

NSCLC) that has not responded tochemotherapy.


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mechanism of action:


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When the epidermal growth factor (EGF) attaches

to the receptor, it causes an enzyme called tyrosine

kinase (TK) to trigger chemical processes inside thecell to make it grow and divide.

Iressa attaches itself to the EGF receptor on the celland prevents the receptor from being activated. This

stops the cells from dividing.

Iressa is taken as a tablet once a day.

The tablet should be taken at roughly the same timeeach day.

Side effects:


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Side effects:

1- Diarrhea 2- Acne-like rash

3- Loss of appetite 4-nausea & vomiting

5-Change in blood pressure Iressa maymake your blood pressure rise,

6-Breathing problems A rare side effect ofgefitinib is inflammation of the lungs


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Gene Therapy

for Cancer


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ancer gene therapy: fourseparate pathways have

developed, namely :-

1- immuno-therapy2- introduction of tumor suppressor

genes\ induction of apoptosis

3- enzyme prodrug therapy4- inhibition of tumors angiogenesis.

:


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I- immunotherapy:-tumors do express antigen that can be recognized by

the immune system:-

A- unique antigen expressed only by individualtypes of tumor (e.g bcr\abl in CML)

B- shared tumor specific antigens (e.g CEA) C- tissue specific antigen expressed by both the

tumor & the healthy tissue ( e.g tyrosinase inmelanoma)

D- viral antigens in known viral associatedtumors ( e.g human papilloma virus E6 protein incervical cancer )

tumor cells are able to evade the


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tumor cells are able to evade the

immune system through several

mechanisms:-

1- Secretion of inhibitory factors such as transforminggrowth factor (TGF)

2- down regulation ofMHC class I & II

3- disrupted antigen-presentation pathway

4- the ability to induce T-cell apoptosis


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immunotherapy

theinduction of

cytokine

Genetic modification

of lymphocytes

Tumorantigen

vaccines


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A) Induction of cytokine or co-

stimulatory molecule expression:-

The frequently employed cytokines includeinterleukin2 ( IL-2), interleukin 12 ( IL-12)

& granulocyte-macrophage colony-stimulating factor (GM-CSF).

Many clinical protocols involve an ex vivoapproach

excision of a single tumor nodule, viraltransduction in vitro, followed by selectionfor the transgene, irradiation of the modifiedcells & finally re-implantation.

The hope is that a generalized antitumour


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p gimmune response will be elicited.

In theory, the cytokines could be administeredsystemically, removing the need for viralmodification. However, the level of systemiccytokine required to induce an antitumour

response inevitably produces systemictoxicity.

The ex vivo approach permit the localproduction of high concentration cytokinewithin the microenvironment of the tumor,without significant systemic level beingproduced .


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1- interleukin 2 ( IL-2) secreted mainly by activated T-helper ( Th) cells

stimulates the proliferation & activation of a wide

variety of cells including cytotoxic T lymphocytes( CTLs), natural killer ( NK) cells & lymphokine-

activated killer ( LAK) cells

induction of IL-2 expression by a variety of tumor

cells leads to tumor rejection mediated by CLTs& NK cells .


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2- interleukin 12( IL-12) expressed mainly be activated macrophages

its main function is the promotion of a Th1- like

response via the secretion of interferon ( IFN) ,

IL-2, and tumor necrosis factor ( TNF ) this is

in turn promotes cell-mediated immunity .

induction of IL-12 secretion can result in

regression of a wide variety of tumors with thedevelopment of protective immunity against re-

challenge.

3- Granulocyte-macrophagecolon stim lating factor (GM


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colony-stimulating factor (GM-

CSF).

The main function of GM-CSF is to causematuration of Antigen-presenting cells(APCs).

APCs detect antigens released by tumorcells processing them & presenting them inassociation with class I & class II MHC toT-cells in local lymph nodes there by

eliminating the need for the tumor topresent antigens directly by itself.

B) Genetic modification of


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)

lymphocytes:-

The strategy here is to modify the lymphocytes,rather than the tumor cells

Currently extremely popular is the modification ofdenderitic cells (DCs)

DCs cells are bone marrow-derived cells function asextremely potent APCs and capable of activating T-cells.

Intratumoural injection of DCs modified with anadenovirus encoding CD40 ligand led to significanttumor regression in a murine model

II- Introduction of tumor suppressor


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pp

genes & induction of apoptosis:-

multiple genes are involved in carcinogenesis, butmutations of the p53 gene are the most frequent

abnormality identified in human tumors

Preclinical studies both in vitro and in vivo haveshown that restoring p53 function can induce

apoptosis in cancer cells.

High levels ofp53 expression and DNA-damaging

agents like cisplatin and ionizing radiation worksynergistically to induce apoptosis in cancer cells.

Phase I clinical trials now show that p53


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p

gene replacement therapy using both

retroviral and adenoviral vectors isfeasible and safe.

In addition, p53 gene replacement

therapy induces tumor regression inpatients with advanced non-small-cell

lung cancer (NSCLC) and in those with

recurrent head and neck cancer.

III- Virus-directed


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enzyme\prodrug therapy:-

The principle is to achieve tumor cellselectiveactivation of prodrugs and to produce tumor-specificcytotoxicity

Potentially, one of several "vectors" (antibodies,

viruses, or neural progenitor cells) can be used todeliver a prodrug-activating enzyme selectively totumor foci in vivo

the elevated level of enzyme at the tumor foci

produce high local concentrations of active drug,increasing the antitumor effect and decreasing thetoxicity of the systemically given prodrug.


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The search for more efficient prodrug-activating


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p g genzymes/prodrugs for the treatment of cancer has ledto investigations of a variety of combinations,

including :

1- Herpes simplex virus-thymidinekinase/ganciclovir

2- Escherichia coli cytosine deaminase/5-fluorocytosine

3- E. coli purine nucleoside phosphorylase/2-fludarabine

4- cytochrome P450reductase/cyclophosphamide

conclusion


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conclusion

1- Several lines of evidence support the idea is theresult ofgenetic changes in somatic cells.

2- Two major types of genes that contribute tomalignant change: oncogenes & tumorsuppressor genes.

3- Oncogenes are normal cellular genes(protoncogens) that when activated by mutationleads to abnormal growth causing malignacy.

4- oncogenes encode proteins that are involved in


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the signal transduction pathways involved in

stimulation ofcell growth

.

5- tumorsuppressor genes encode proteins

involved in regulation of growth.

6- tumor suppressor genes contributes to

transformation to cancer when both alleles aremutated . In some cases one is inherited & the

other acquired somatically.

7 i t d li i


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7- progression towards malignancy is

multistep process due to gradual

accumulation of genetic changes including

activation of oncogenes and loss of

function of tumor suppressor genes.

8- knowledge ofthe molecular basis of

cancer is used to develop methods ofdiagnosis and new treatment.


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Thank you


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cancergenesandgrowthfactors-100301173509-phpapp01

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