PowerPoint Presentation

Sufyan AkramMBBS PhDPrinciples of Cancer ChemotherapyNational Cancer Institutes website (an excellent resource):http://www.cancer.gov/

What is Cancer?Cancer is a diverse class of diseases which differ widely in their causes and biology

Any organism, even plants, can acquire cancer

Nearly all known cancers arise gradually, as errors build up in the cancer cell and its progeny

What is Cancer?Cancer is a complex disease characterized by deregulation of cell proliferation and apoptotic mechanisms, stromal and microenvironmental changes, angiogenesis and cell metastasis

IncidenceAccording to the American Cancer Society, 7.6million people died from cancer in the world during 2007

Cell CycleStarting from a single-celled zygote An adult human being has approximately 100,000 billion cellsCell division does not stop with formation of mature organism, but continues throughout its life

Tens of millions of cells undergo division at any given moment in an adult human. This amount of division is needed to replace cells that have aged or died

The Eukaryotic Cell CycleMost eukaryotic cells will pass through an ordered series of events in which the cell duplicates its contents and then divides into two cells

This process of cell division in multicellular organisms must be highly ordered and tightly regulated

MSG2G1

G0G2 Checkpoint

G1 Checkpoint

Metaphase Checkpoint

Is cell big enough?Is environment favourable?Is all DNA replicated?Is cell big enough?Is environment favourable?Are all chromosomes aligned on spindle?

How Cancer Develops?Cancer arises from a loss of normal growth control. In normal tissues, the rates of new cell growth and old cell death are kept in balance. In cancer, this balance is disruptedThis disruption can result from uncontrolled cell growth or loss of a cells ability to undergo cell suicide by a process called apoptosis

Apoptosis, or cell suicide, is the mechanism by which old or damaged cells normally self-destruct

How Cancer Develops?Cancer cells do not respond normally to bodys control mechanisms:

Ignore density dependent inhibition, cells continue to multiply until nutrients are exhausted

Divide excessively and invade other tissues

Loss of normal growth control

Cancer cell divisionFourth orlater mutationThird mutationSecond mutationFirst mutationUncontrolled growthCell Suicide or ApoptosisCell damage that couldnt be repairedNormal cell division

Example of normal growth

Cell migrationDermisDividing cells in basal layerDead cells shed from outer surface

Epidermis

Cancerous growth

Underlying tissue

Benign vs Malignant neoplasms

Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sitesTimeBenign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis

Properties of Cancer CellUnchecked growthLoss of capacity for apoptosis (growth despite genetic errors and external anti-growth signals) Loss of capacity for senescence (immortality) Sustained angiogenesis Invasion of neighbouring tissues

Acquisition of ability to build metastases at distant sites, the classical property of malignant tumours

What causes Cancer?

Genes and Cancer

Chromosomes are DNA moleculesHeredity

Radiation

ChemicalsViruses

Tumour Suppressor Genes

Normal genes prevent cancerRemove or inactivate tumor suppressor genesMutated/inactivated tumor suppressor genesDamage to both genes leads to cancerCancer cellNormal cell

Oncogenes

Mutated/damaged oncogeneOncogenes accelerate cell growth and divisionCancer cellNormal cellNormal genes regulate cell growth

Cancer tend to involve multiple mutationsMalignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sitesMore mutations, more genetic instability, metastatic diseaseProto-oncogenes mutate to oncogenesMutations inactivate DNA repair genesCells proliferateMutation inactivates suppressor geneBenign tumor cells grow only locally and cannot spread by invasion or metastasis

Time

Causative/ Contributing Factors

Some viruses or bacteriaHeredityDietHormones

Radiation

Some chemicals

Examples of Human Cancer Viruses

Occupational Carcinogens

Some Carcinogens in the Workplace

Types of Cancer

LungBreast (women)

ColonBladderProstate (men)Some common sarcomas:FatBoneMuscleLymphomas:Lymph nodesLeukemias:Bloodstream

Some common carcinomas:

Types of CancerCarcinomas, the most common types of cancer, arise from the cells that cover external and internal body surfaces. Lung, breast, and colon are the most frequent cancers of this typeSarcomas are cancers arising from cells found in the supporting tissues of the body such as bone, cartilage, fat, connective tissue, and muscleLymphomas are cancers that arise in the lymph nodes and tissues of the bodys immune systemLeukemias are cancers of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream

Why cancer is dangerous?

Melanoma cells travel through bloodstreamMelanoma(initial tumor)BrainLiver

Early cancer is usually symptom-lessMajor problem in detecting and treating cancer is its late presentation

Various screening programs has been proposed and implemented but without much success

Major emphasis on prevention !!!

Symptoms & Complications

LocalUnusual lumps or swelling (tumour)Haemorrhage (bleeding)Pain and/or ulcerationCompression of surrounding tissues may cause pressure symptoms

ErosionAngiogenesis

Symptoms of metastasisEnlarged lymph nodesCough and haemoptysisHepatomegaly (enlarged liver)Bone pain, fracture of affected bonesNeurological symptoms

Although advanced cancer may cause pain, it is often not the first symptom

SystemicWeight lossPoor appetiteFatigue and cachexia (wasting)Excessive sweating (night sweats)Anaemia

Specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as ectopic production of hormones by cancer cells

Cancer Treatment

3 Major Modalities of RxChemotherapyRadiation TherapySurgery

Multidisciplinary ApproachCancer treatment requires the cooperation of a multidisciplinary team to coordinate the delivery of the appropriate treatment (surgery, chemotherapy, radiotherapy and biological/endocrine therapy), supportive and symptomatic care, and psychosocial support

ChemotherapyConventional chemotherapy kills all rapidly dividing cells

High (and sometimes toxic) doses of these drugs are usually given with the hope that all cancer cells will be killed

An unavoidable consequence of this approach is killing of normal actively dividing cellse.g., Hair follicles, Bone Marrow, GI Mucosa

Major Side EffectsThis results in the most common side effects of chemotherapy:myelosuppression (decreased production of blood cells, hence also immunosuppression),mucositis (inflammation of the lining of the digestive tract), andalopecia (hair loss)Other serious side effects are:Severe Nausea and VomittingInfertilitySecondary Tumors

Classes of DrugsAlkylating AgentsAntimetabolitesAnthracyclinsPlant AlkaloidsTopoisomerase InhibitorsCytotoxic Antibiotics

1. Alkylating AgentsAlkylating agents act by covalently binding alkyl groups, and their major effect is to cross-link DNA strands, interfering with DNA synthesis and causing strand breaksDespite being among the earliest cytotoxic drugs developed, they maintain a central position in the treatment of cancer

They work by chemically modifying a cell's DNA

2. AntimetabolitesAnti-metabolites masquerade as purines or pyrimidinesThey prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division

They also affect RNA synthesisDue to their efficiency, these drugs are the most widely used cytostatics

Antimetabolites (contd)Folic acid antagonistmethotrexatePyrimidine antagonists5-Fluorouracil (5-FU)Arabinosides inhibit DNA synthesis by inhibiting DNA polymeraseCytosine arabinoside (cytarabine)Purine antagonists6-mercaptopurine and 6-tioguanine

3. AnthracyclinsAnthracyclines (or anthracycline antibiotics) are a class of drugs derived from Streptomyces bacteria

The anthracyclines are some of the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapy agentsTheir main adverse effects are heart damage (cardiotoxicity), which considerably limits their usefulness

Anthracyclins (contd)Mechanisms of Action:1.Inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells2.Inhibit topoiosomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication3.Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes

4. Plant AlkaloidsThese alkaloids are derived from plants and block cell division by preventing microtubule function

The main examples are vinca alkaloids and taxanes

Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle)Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase

5. Topoisomerase InhibitorsInhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling

6. Cytotoxic AntibioticsThese include doxorubicin, epirubicin, bleomycin and others

Have different mechanisms of action:Doxorubicin works by intercalating DNABleomycin works by causing breaks in DNA

Chemotherapy RegimenMost tumours rapidly develop resistance to single agents given on their own. For this reason the principle of intermittent combination chemotherapy was developed

Several drugs are combined together

These drugs are given over a period of a few days followed by a rest of a few weeks, during which time the normal tissues have the opportunity for re-growth

Response to ChemotherapyAs chemotherapy affects cell division, tumors with high growth fractions (such as acute leukemia and the aggressive lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time

Malignancies with slower growth rates do not tend to respond to chemotherapy

Targeted TherapyNewer anticancer drugs act directly against abnormal proteins in cancer cells; this is termed targeted therapy

Any Examples??

Targeted TherapyThe first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormone estrogen, which many breast cancers require for growthWhen estrogen binds to the estrogen receptor (ER) inside cells, the resulting hormone-receptor complex activates the expression of specific genes, including genes involved in cell growth and proliferation

Tamoxifen was the first drug developed as a targeted therapy

Signal Transduction InhibitorsImatinib mesylate (Gleevec) is approved to treat gastrointestinal stromal tumor (a rare cancer of the gastrointestinal tract) and certain kinds of leukemia

It targets several members of tyrosine kinase enzymes that participate in signal transduction

In SummaryCancer is a heterogeneous group of diseases, with wide range of causative factors

Cancer treatment requires the cooperation of a multidisciplinary team (surgery, chemotherapy, radiotherapy and biological/ endocrine therapy)

The improved understanding of molecular biology and cellular biology due to cancer research has led to a number of new and effective treatments

ReferencesNational Cancer Institutes websitehttp://www.cancer.gov/

Lippincott Illustrated Reviews: Pharmacology 5th ed (2011)

Thank you