Cancer Cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs.

Human Genome Project data

• We are all 99.9% similar in our DNA. • Individuals vary by only 0.1%

• Individual variations may correlate with different responses to medicines and magnitude of disease risk.

Cancer Cancer: a group of related diseases characterized by cells growing out of control.Mutated genes that cause cancer are called oncogenes.

Tumour cells travel - metastasis

• What makes most tumors so lethal is their ability to metastasize -- that is, establish new tumour sites at other locations throughout the body.Secondary tumours.

• Metastasis is now underway, as tumour cells from the original cancer growth travel throughout the body. Most of these cells will die soon after entering the blood or lymph circulation.

• A tumour i.e. is not capable of indefinite growth and does not invade the healthy surrounding tissue extensively is BENIGN.

• A tumour that continues to grow and becomes progressively invasive is MALIGNANT.

• Malignant tumors exhibit METASTASIS.

Metastasis

• To form a secondary tumour, a tumour cell needs to leave the vessel system and invade tissue. The cell must attach itself to a vessel's wall. Once this is done, it can work its way through the vessel and enter the tissue.

Although perhaps less than one in 10,000 tumour cells will survive long enough to establish a new tumour site, a few survivors can escape and initiate new colonies of the cancer.

• Metastasis ---- Cancer cells sometimes invade surrounding tissues, often breaking through the basal laminae to establish secondary areas of growth.– Metastatic tumors often secrete proteases, which degrade the surrounding

extracellular matrix.– Both primary and secondary tumors require angiogenesis, the formation of new

blood vessels, in order to grow to a large mass.• The multi-hit model proposes that multiple mutations are needed to

cause cancer.

• Cancers as a group account for approximately 13% of all deaths each year with the most common being: lung cancer (1.3 million deaths), stomach cancer (803,000 deaths), colorectal cancer (639,000 deaths), liver cancer (610,000 deaths), and breast cancer (519,000 deaths).

The three most common cancers Men: Prostate, lung, and colorectalWomen: Breast, colorectal, and lungChildren: leukemia (34%), brain tumors (23%), and lymphomas (12%).

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths.

Risk Factors

Growing olderTobaccoSunlight

Ionizing radiationchemicals and other substances

Some viruses and bacteriahormones

Family history of cancerAlcohol

Poor diet, lack of physical activity, overweight

There are five broad groups that are used to classify cancer.• CARCINOMAS: cells that cover internal and external parts of the body -

lung, breast, and colon cancer.

• SARCOMAS: cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues.

• LYMPHOMAS are cancers that begin in the lymph nodes and immune system tissues.

• LEUKEMIA are cancers that begin in the bone marrow and often accumulate in the bloodstream.

• ADENOMAS are cancers that arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.

Properties of cancer cells

• Lack of density dependent inhibition [autocrine growth factor production and stimulation]. Hence no requirement for growth factors.

• Less adhesive than normal cells [no contact inhibition].

• Resistant to signals that normally program cell death (apoptosis).

Local symptoms: are restricted to the site of the primary cancer.

• lumps or swelling (tumor), • hemorrhage ( skin, mouth or anus),• ulceration and pain.

Metastatic symptoms: due to the spread of cancer to other locations .

• lymph nodes • hepatomegaly or splenomegaly • neurological symptoms.

Systemic symptoms: due to distant effects of the cancer ,not related to direct or metastatic spread. • weight loss (poor appetite and cachexia)• Fatigue• excessive sweating (especially night sweats)• anemia

The anorexia –cachexia syndrome is typical of patients suffering from many tumor and occurs in greater than 50% of all cancer patients and more than 85% of pancreatic and lung cancer patients (Tisdale,2005

• 1942 - Louis Goodman and Alfred Gilman used nitrogen mustard to treat lymphoma

• 1948 - Sydney Farber used successfully methotrexate to cure children with acute leukemia

• 1955 - The Chemotherapy Program begins • 1975 – A combination of cyclophosphamide, 5-fluorouracil and

methotrexate was show as an effective treatment of breast cancer• 1978 - FDA approves cisplatin against ovarian cancer• 1998 - FDA approves paclitaxel (Taxol), which becomes the first

oncology “blockbuster” drug• 2001 - FDA approves imatinib (Glivec).

Beginning the era of targeted therapy

• Bacterial treatments• Drug therapies• Insulin potentiation therapy• Virotherapy and Oncolytic virus• Telomerase therapy• Photodynamic therapy• Hyperthermia therapy• Non-invasive RF cancer treatment• Complementary and alternative treatments(CAM)

Cancer treatment depends on the type of cancer, the stage of the cancer, age, health status, and additional personal characteristics.

It is combination of therapies and palliative care

Methods used for cancer treatment

Technical Challengesin treatment of cancer

• Radiation therapy (radiotherapy or radiation oncology), is the medical use of ionizing radiation as part of cancer treatment to control malignant cells

• Radiotherapy is used for the treatment of malignant tumors (cancer), and the primary therapy. It is also common to combine radiotherapy with surgery, chemotherapy, hormone therapy or some mixture of the three.

Mode of action• Radiation therapy works by damaging the DNA of cells. The damage is

caused by a photon, electron, proton, neutron, or ion beam directly or indirectly ionizing the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA.

• Chemotherapy, in its most general sense, refers to treatment of disease

by chemicals that kill cells, both good and bad, but specifically those of

micro-organisms or cancer.

• In the broad sense, most chemotherapeutic drugs work by impairing

mitosis (cell division), effectively targeting fast-dividing cells. As these

drugs cause damage to cells they are termed cytotoxic. Some drugs cause

cells to undergo apoptosis ( "programmed cell death").

anti-oxidants ?• Antioxidants are substances that protect cells from the damage caused by

unstable molecules known as free radicals. • Free radical damage lead to cancer.

• Antioxidants interact with and stabilize free radicals and prevent damage caused by free radicals.

• Research study in 2003 suggests that adding antioxidants to chemotherapy can kill more cancer cells than either treatment alone when administered to cells in laboratory(Pathak,2002)

Lipid Replacement Therapy administered as a nutritional supplement with antioxidants can prevent oxidative membrane damage to normal tissues, restore mitochondrial and other cellular membrane functions and reduce the adverse effects of cancer therapy.

Recent clinical trials have shown the benefit of Lipid Replacement Therapy plus antioxidants in restoring mitochondrial electron transport function and other cellular membranes from oxidative damage.

• Thus dietary supplementation with antioxidants and some accessory molecules, such as zinc and certain vitamins, are important in maintaining antioxidant and free radical scavenging systems.

Roche Chip for Cytochrome P450Genes: CYPC19 and CYP2D6

Xie and Frueh, Pharmacogenomics steps toward Personalized Medicine, Personalized Medicine 2005, 2, 325-337

The world's first microarray-based pharmacogenomic test cleared for clinical use.

The AmpliChip CYP450 Test provides comprehensive detection of gene variations — including deletions and duplications — for the CYP2D6 and CYP2C19 genes, which play a major role in the metabolism of an estimated 25% of all prescription drugs. It is intended to be an aid to clinicians in determining therapeutic strategy and treatment dose for therapeutics metabolized by the CYP2D6 or CYP2C19 gene product.

Field of pharmacogenetics

• First emerged around the 1950’s

• Scientists began to notice that different responses to drugs ran in families and ethnic groups.

• Evaluates how an individual’s genetic makeup corresponds to the response to a particular medication

• Tailors medical treatments to the individual increasing their effectiveness while reducing side effects

• The goal of pharmacogenomics (personalised medicine) is the right dose of drug

to the patient at right time

PHARMACOGENOMICS AND CANCER

AnemiaAppetite changesBleeding problemsConstipationDiarrheaFatigueAlopeciaInfectionMemory changesNausea and vomitingWater retention

Gene expression: application to cancer• Create diagnostic tests to predict

whether a patient has a genetic predisposition to cancer – Examine the DNA sequence of a person's

cancer-related genes to detect genetic signatures that predict a predisposition to cancer.

– Examine a tissue sample for abnormal gene expression patterns that indicate a predisposition to cancer.

• Design drugs intended to treat or

prevent cancer. – Develop drugs that inhibit the function of

proteins related to cancer.

• Design drugs to control expression of cancer genes.– Drugs would interact directly with DNA in

key cells and tissues to prevent genes from being turned on or off.

Benefits of pharmacogenetics

• New, more accurate diagnostic tests– Predict a patient's response to specific drugs

based on his or her genetic profile. •Personalized drug therapies

–Match a patient with effective and safe medications based on information from diagnostic tests.

•Personalized disease prevention strategies

–Developed using genetic tests that estimate a patient's risk of getting a particular disease, combined with personalized drug therapies.

Cancer :Preventive measures

Tobacco controlVaccinationEarly detection/treatmentHealth campaignsPromoting physical activityHealthier dietary intake

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