Cancer Genes And Growth Factors

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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 represents the collapse of the cooperation between the ten million cells of human being . This results in the selfish, uncontrolled growth of cells within the body which eventually leads to the death of the organism.

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History of Cancer-:

• Cancer as described by the ancient Egyptians (3000 BC to 1500 BC):-

• The oldest known description of human cancer is found in an Egyptian seven papyri 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 considered

the father of medicine, is though to be the first person to clearly recognize difference between benign and malignant tumors.

• Hippocrates noticed that blood vessels around a

malignant tumor looked like the claws of crab. He named the disease karkinos (the Greek name for crab)

• In English, this term translates to carcinos or carcinoma.

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• Later in the course of history, the cause of 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 same period Gaspare Aselli discovered the lymphatic system

• New theory suggested that abnormalities in the lymph and lymphatic system as the primary cause of cancer.

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• Discovery of anesthesia in 1844 by Wells allowed surgery to flourish and the classic cancer operations such as radical mastectomy were developed.

• The discovery of microscope by Leeuwenhoek in the late 17th century added momentum to the quest for the cause of cancer.

By late19th century, with the development of better 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 the founder of cellular pathology, provided the scientific basis for the modern pathologic study of cancer and correlated the clinical course of illness with microscopic findings.

• This approach led to the development of modern cancer surgery

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**Cancer is a genetic disorder-:

• Four lines of evidence converged to demonstrate that cancer is a genetic disease:-

• 1- Chromosomal anomalies in cancer:-

in chronic myelogenous leukemia (CML) translocation between chromosome 9 & chromosome 22 forming Philadelphia chromosome

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• 2- Families in which cancer is transmitted as a genetic trait e.g. Li-Fraumeni Syndrome, inherited as autosomal dominant trait.

• 3- Overlap between carcinogens & mutagens.

• 4- Individuals with DNA repair deficiency syndrome are at increased risk of cancer e.g Xeroderma pigmentosum, inability to repair DNA damage done by U.V exposure leads to high 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 tell the cell to make an abnormal protein, which no longer functions properly

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

• Some diseases like sickle cell anemia are caused 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. This type of mutation is a major factor for 5% to 10% of cancers.

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2 -Acquired mutations-:

• occurs when DNA in a cell changes during the person’s life.

• caused by environmental influences such as exposure to radiation or toxins.

• they are not in the reproductive cells.

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

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• mutations in our cells happen all the time

• our genes can recognize and repair the abnormality

• If it can’t be repaired, the cell will actually begin a process called apoptosis that leads to its death.

• If the mutation occurs in a gene that helps control how often a cell divides or one that checks for errors in cell division, it may contribute to a person developing cancer.

• cancer may also occur because the mutation happens 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 that makes him or more likely to develop a specific type of cancer.

• On top of this, he may acquire other mutations because of exposure to cigarette smoke, excess sunlight, or viruses.

• Therefore, some people may be more likely to develop 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 main types of genes that are now recognized as playing a role in cancer are oncogenes and tumor suppressor genes.

**What Are Oncogenes?

- Oncogenes are 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 the cell 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" or activated

• 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 a way

that is similar to a gas pedal An oncogene could be compared to a gas pedal that is stuck down, → cell to divide out of control

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Pathway of normal cell growth-:

• starts with growth factor, which locks onto a growth factor receptor.

• The signal from the receptor is sent through a signal transducer.

• A transcription factor is produced, which causes the cell to begin dividing.

• More than 100 oncogenes are now recognized Scientists have divided oncogenes 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 protein

called platelet-derived growth factor (PDGF), which stimulates cells to grow.

• Vascular endothelial growth factor (VEGF) & Fibroblast growth factor (FGF) are other growth 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. They may become always in the on state in 2 cases:-

• a- Certain mutations in the genes that produce them.

• b- gene amplification: This means that instead of the usual 2 copies of the

gene, there may be several extras, resulting in too many growth factor receptor molecules.

• The best-known examples of growth factor receptor gene amplification are erb B and erb B-2.

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3 -Signal transducers • These are the intermediate pathways between the

growth factor receptor and the cell nucleus where the 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 and

is the target of the most successful drug for this disease, imatinib or Gleevec. Abnormalities of ras

are 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 which

genes are active in producing RNA and protein.• The best known of these is called myc. In lung

cancer, leukemia, lymphoma, and a number of other 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 committing suicide when it becomes abnormal

• When these genes are overactive, they prevent the 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 is

often 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 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 RB1.

• A tumor suppressor gene is like the brake pedal on a car

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• 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.

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Types of Tumor Suppressor Genes

1- Genes that control cell division :-

The RB1 (retinoblastoma) gene is an example of such a gene.

Abnormalities of the RB1 gene can lead to (retinoblastoma) in infants

there are always 2 copies of each gene. But the inherited RB1 mutation only affects one of the gene pairs

during the infant’s development, a random mutation can occur in the normal copy of the RB1 gene. Scientists call this process loss of heterozygosity (LOH)

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2- Genes that repair DNA

• when a cell prepares to divide into 2 new cells, it must duplicate its DNA. copying errors sometimes occur but cells have DNA repair genes, which make proteins that proofread DNA

The genes responsible for HNPCC (hereditary nonpolyposis colon cancer) are examples of DNA

repair gene defects. When these genes do not repair the errors in DNA, HNPCC can result. HNPCC

accounts for up to 5% of all colon cancers and some endometrial cancers.

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3- Cell "suicide" genes :-• If there is too much damage to a cell’s DNA

couldn't be repaired by DNA repair system• Cell is directed to be destroyed what is called

(programmed cell death or apoptosis )• the p53 tumor suppressor gene is responsible

for this 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

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• Abnormalities of the p53 gene are sometimes inherited, such as in the Li-Fraumeni syndrome (LFS).

• People with LFS have a higher risk for developing a number of cancers, including soft-tissue and bone sarcomas, brain tumors, breast cancer, adrenal gland cancer, and leukemia.

Many sporadic (not inherited) cancers such as lung cancers, colon cancers, breast cancers

as well as others often have mutated p53 genes within the tumor.

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Inherited Abnormalities of Tumor Suppressor Genes

• In addition to mutations in p53, RB1, and the genes involved in HNPCC, several other mutations in tumor suppressor genes can be inherited.

• A defective APC gene causes familial polyposis, a condition in which people develop hundreds or thousands of colon polyps

• Abnormalities of the BRCA genes account for 5% to 10% of breast cancers.

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Non-inherited mutations of tumor suppressor genes

• Mutations of tumor suppressor genes have been found in many cancers.

• abnormalities of the p53 gene have been found in over 50% of human cancers.

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

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

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Inherited cancer Abnormal gene Other non-inherited

cancers seen with this gene

RetinoblastomaRBIMany different cancers

Li-Fraumeni Syndrome (sarcomas, brain tumors, leukemia)P53Many different cancers

MelanomaINK4aMany different cancers

Colorectal cancer (due to familial polyposis)APCMost colorectal cancers

Colorectal cancer (without polyposis)MLH1, MSH2, or MSH6Colorectal, gastric, endometrial cancers

Breast and/or ovarianBRCA1, BRCA2Only rare ovarian cancers

Wilms TumorWTIWilms tumors

Nerve tumors, including brainNF1, NF2Small numbers of colon cancers,

melanomas, neuroblastoma

Kidney cancerVHLCertain types of kidney cancers

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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 risk for developing cancers.

• Genetic testing can be used to look for such mutations.

• The testing is often expensive • Finding a genetic mutation can have a

significant impact on a person’s 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 to benefit 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 sensitive in 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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Oncogene/Tumor Suppressor Gene

Related Cancers

BRCA1, BRCA2Breast and ovarian cancer

bcr-ablChronic myelogenous leukemia

bcl-2B-cell lymphoma

HER2/neu (erbB-2)Breast cancer, ovarian cancer, others

N-mycNeuroblastoma

EWSEwing tumor

C-mycBurkitt lymphoma, others

p53Brain tumors, skin cancers, lung cancer,

head and neck cancers, others

MLH1, MSH2Colorectal cancers

APCColorectal cancers

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How Can Oncogenes and Tumor Suppressor Genes Be Used to

Treat 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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How it is given ?How it is given ?

Herceptin is given by a drip Herceptin is given by a drip (infusion(infusion ) )The first dose is given slowly, usually over about The first dose is given slowly, usually over about

an hour and a halfan hour and a half. After this, doses normally . After this, doses normally take about take about 30 minutes30 minutes. . The drug may be given The drug may be given onceonce a week or once a week or once every three weeksevery three weeks. .

If Herceptin is given together with If Herceptin is given together with TaxolTaxol or or Taxotere, they are given in the normal way, Taxotere, they are given in the normal way, which is usually which is usually every three weeks.every three weeks.


UsesUses-:-:

Herceptin Herceptin is used mainly to treat women with is used mainly to treat women with breast cancerbreast cancer

It may be used in the It may be used in the early stagesearly stages to increase to increase the chances of a curethe chances of a cure

It also used in It also used in metastatic breast cancermetastatic breast cancer

In most cases it is used in In most cases it is used in combinationcombination with with chemotherapeutic agents chemotherapeutic agents paclitaxel or paclitaxel or docetaxeldocetaxel


Side effects:Side effects:

1- Effects on the heart:1- Effects on the heart:

Herceptin may lead to Herceptin may lead to cardiomyopathycardiomyopathy or congestive or congestive heart failure sprcially if taken with heart failure sprcially if taken with carboplatincarboplatin, , it it is recommended that Herceptin is not given to is recommended that Herceptin is not given to people with a history of heart disease or high blood people with a history of heart disease or high blood pressure.pressure.

2- Flu-like symptoms2- Flu-like symptoms

This includes a high temperature (This includes a high temperature (feverfever) and chills, ) and chills, shortly after the drug is given. shortly after the drug is given.


3- Tumour pain:3- Tumour pain: Some people may experience mild Some people may experience mild painpain in parts in parts

of the body to which the breast cancer has of the body to which the breast cancer has spread. spread.

4- Diarrhea4- Diarrhea5- Headaches5- Headaches 6- Allergic reactions6- Allergic reactions:: This is a rare side effect of Herceptin. Signs of This is a rare side effect of Herceptin. Signs of

this include skin this include skin rashes and itchingrashes and itching, , wheezing, difficulty breathing, and wheezing, difficulty breathing, and breathlessness.breathlessness.


Cetuximab (Erbitux®)Cetuximab (Erbitux®)


a monoclonal antibodya monoclonal antibody, In the UK it is , In the UK it is currently used to treat cancer of the currently used to treat cancer of the colon and colon and rectumrectum specially advanced or metastatic specially advanced or metastatic cancer.cancer.

cetuximab is given in combination with the drug cetuximab is given in combination with the drug irintocan irintocan . Cetuximab is also used with . Cetuximab is also used with radiotherapyradiotherapy to treat locally to treat locally advanced head advanced head and neck cancer.and neck cancer.

Cetuximab is also being used in research trial to Cetuximab is also being used in research trial to treat other types of cancer, including non-small treat other types of cancer, including non-small cell lung cancer cell lung cancer (NSCLC(NSCLC) and ) and breastbreast cancer. cancer.


Mechanism of action:Mechanism of action:


Cetuximab Cetuximab attaches to the attaches to the EGFRsEGFRs and and prevents the receptors from being activated. prevents the receptors from being activated.

This This stopsstops the cells from dividing. therefore the cells from dividing. therefore stop the cancer cells from stop the cancer cells from growing.growing.

Cetuximab also make the cancer cells more Cetuximab also make the cancer cells more sensitive to chemotherapy and radiotherapysensitive to chemotherapy and radiotherapy

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


Dosage and Dosage and administrationadministration::

Cetuximab is a Cetuximab is a colourless liquidcolourless liquid

Cetuximab is given by a drip into the vein Cetuximab is given by a drip into the vein ((intravenouslyintravenously) through cannula. The first dose is ) through cannula. The first dose is given given slowlyslowly, usually over two hours., usually over two hours.

After this, doses are given After this, doses are given weeklyweekly and this normally and this normally

takes about takes about an houran hour. The first dose is usually larger . The first dose is usually larger than the weekly maintenance treatments.than the weekly maintenance treatments.


Possible side effectsPossible side effects:-:-1-1-Allergic reactionsAllergic reactions skin rashes and itching, a skin rashes and itching, a

feeling of swelling in the tongue or throatfeeling of swelling in the tongue or throat antihistaminesantihistamines can be given can be given

2- 2- nauseanausea and less commonly and less commonly vomiting vomiting

3- 3- Diarrhea Diarrhea This can usually be controlled with This can usually be controlled with medicinemedicine

4- 4- Fever and chillsFever and chills

5- 5- dyspneadyspnea Some people may become breathless Some people may become breathless


PertuzumabPertuzumab also called also called 2C42C4, formerly known as , formerly known as OmnitargOmnitarg is a is a

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

By binding to HER2, it inhibits the dimerization of By binding to HER2, it inhibits the dimerization of HER2 with other HER receptors, which is HER2 with other HER receptors, which is hypothesized to result in hypothesized to result in slowed tumor growthslowed tumor growth..

Early clinical trials of pertuzumab in Early clinical trials of pertuzumab in prostate, prostate, breast, and ovarian cancersbreast, and ovarian cancers have been met with have been met with limited successlimited success..

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ImatinibImatinib (Gleevec®)(Gleevec®)


It is used in treating It is used in treating chronic myelogenous chronic myelogenous leukemialeukemia ( (CMLCML), ), gastrointestinal stromal gastrointestinal stromal tumorstumors ( (GISTsGISTs) and a number of other ) and a number of other malignancies.malignancies.

It is the first member of a new class of agents It is the first member of a new class of agents that act by inhibiting particular that act by inhibiting particular tyrosine tyrosine kinase enzymekinase enzyme, instead of non-specifically , instead of non-specifically inhibiting rapidly dividing cells.inhibiting rapidly dividing cells.

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Mechanism of action:

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• Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), and PDGF-R (platelet-derived growth factor receptor).

• In chronic myelogenous leukemia , the philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a continuously active tyrosine kinasae, imatinib is used to decrease bcr-abl activity.

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Uses

1- Imatinib is used in chronic myelogenous leukemia 2- gastrointestinal stromal tumors (GISTs)

3- 3- number of other malignancies as certain brain tumors such as high grade gliomas including recurrent glioblastoma

4- Recent mouse animal studies at Emory Univerty in Atlanta have suggested that imatinib may be useful in treating Small pox

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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 their myocardium.

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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 to chemotherapy.

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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 the cell to make it grow and divide.

• Iressa attaches itself to the EGF receptor on the cell and 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 time

each day.

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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 may make your blood pressure rise,

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

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Gene Therapy for Cancer

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Cancer gene therapy-:

• four separate pathways have developed, namely :-

1- immuno-therapy 2- introduction of tumor suppressor

genes\ induction of apoptosis 3- enzyme prodrug therapy 4- 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 individual types 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 in melanoma)

• D- viral antigens in known viral associated tumors ( e.g human papilloma virus E6 protein in cervical cancer )

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tumor cells are able to evade the immune system through several

mechanisms-:

1- Secretion of inhibitory factors such as transforming growth factor β (TGFβ)

2- down regulation of MHC class I & II

3- disrupted antigen-presentation pathway

4- the ability to induce T-cell apoptosis

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immunotherapy

the induction of cytokine

Genetic modification of lymphocytes

Tumor antigen vaccines

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A) Induction of cytokine or co-stimulatory molecule expression-:

•The frequently employed cytokines include interleukin2 ( IL-2), interleukin 12 ( IL-12) & granulocyte-macrophage colony-stimulating factor (GM-CSF) .

•Many clinical protocols involve an ex vivo approach

•excision of a single tumor nodule, viral transduction in vitro, followed by selection for the transgene, irradiation of the modified cells & finally re-implantation .

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• The hope is that a generalized antitumour immune response will be elicited.

• In theory, the cytokines could be administered systemically, removing the need for viral modification. However, the level of systemic cytokine required to induce an antitumour response inevitably produces systemic toxicity.

• The ex vivo approach permit the local production of high concentration cytokine within the microenvironment of the tumor, without significant systemic level being produced .

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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 γ ( IFNγ) , IL-2, and tumor necrosis factor α ( TNFα ) this is in turn promotes cell-mediated immunity .

• induction of IL-12 secretion can result in regression of a wide variety of tumors with the development of protective immunity against re-challenge.

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3 -Granulocyte-macrophage colony-stimulating factor (GM- CSF). • The main function of GM-CSF is to cause

maturation of Antigen-presenting cells (APCs).

• APCs detect antigens released by tumor cells processing them & presenting them in association with class I & class II MHC to T-cells in local lymph nodes there by eliminating the need for the tumor to present antigens directly by itself .


B) Genetic modification of B) Genetic modification of lymphocytes:-lymphocytes:-

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

Currently extremely popular is the modification of Currently extremely popular is the modification of denderitic cells (DCs)denderitic cells (DCs)

DCs cells are bone marrow-derived cells function as DCs cells are bone marrow-derived cells function as extremely potent extremely potent APCsAPCs and capable of activating and capable of activating T-T-cells. cells.

Intratumoural injection of DCs modified with an Intratumoural injection of DCs modified with an adenovirus encoding CD40 ligand led to significant adenovirus encoding CD40 ligand led to significant tumor regression in a murine model tumor regression in a murine model


II- Introduction of tumor suppressor II- Introduction of tumor suppressor genes & induction of apoptosis:-genes & induction of apoptosis:-

multiple genes are involved in carcinogenesis, but multiple genes are involved in carcinogenesis, but mutations of the p53 genemutations of the p53 gene are the most frequent are the most frequent abnormality identified in human tumors abnormality identified in human tumors

Preclinical studies both in vitro and in vivo have Preclinical studies both in vitro and in vivo have shown that restoring p53 function can induce shown that restoring p53 function can induce apoptosisapoptosis in cancer cells. in cancer cells.

High levels of High levels of p53p53 expression and DNA-damaging expression and DNA-damaging agents like agents like cisplatincisplatin and and ionizing radiationionizing radiation work work synergistically to induce apoptosis in cancer cells. synergistically to induce apoptosis in cancer cells.


Phase IPhase I clinical trials now show that clinical trials now show that p53p53 gene replacement therapy using both gene replacement therapy using both retroviral and adenoviralretroviral and adenoviral vectors is vectors is feasible and safe. feasible and safe.

In addition, p53 gene replacement In addition, p53 gene replacement therapy induces tumor regression in therapy induces tumor regression in patients with advanced non-small-cell patients with advanced non-small-cell lung cancer lung cancer (NSCLC(NSCLC) and in those with ) and in those with recurrent recurrent head and neck cancer.head and neck cancer.

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III- Virus-directed enzyme\prodrug therapy:-

• The principle is to achieve tumor cell–selective activation of prodrugs and to produce tumor-specific cytotoxicity

• Potentially, one of several "vectors" (antibodies, viruses, or neural progenitor cells) can be used to deliver a prodrug-activating enzyme selectively to tumor 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 the toxicity of the systemically given prodrug.

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• The search for more efficient prodrug-activating enzymes/prodrugs for the treatment of cancer has led to investigations of a variety of combinations, including :

• 1- Herpes simplex virus-thymidine kinase/ganciclovir

• 2- Escherichia coli cytosine deaminase/5-fluorocytosine

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

• 4- cytochrome P450 reductase/cyclophosphamide

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conclusion

1 -Several lines of evidence support the idea is the result of genetic changes in somatic cells.

2 -Two major types of genes that contribute to malignant change: oncogenes & tumor suppressor genes.

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

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4 -oncogenes encode proteins that are involved in the signal transduction pathways involved in

stimulation of cell growth .

5 -tumor suppressor genes encode proteins involved in regulation of growth.

6 -tumor suppressor genes contributes to transformation to cancer when both alleles are mutated . In some cases one is inherited & the

other acquired somatically .

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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 of the molecular basis of cancer is used to develop methods of diagnosis and new treatment.


Thank youThank you

Cancer Genes And Growth Factors

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