MP421 L1-5

What are the types of Cancer treatment available?

surgery, chemotherapy, radiation, biologic, targeted, gene therapy

tumor

abnormal growth of cells

Examples of benign tumors

lipoma, skin moles, cysts

Factors effecting chance of getting cancer

Age, gender, race

why is there a higher incidence of cancer in older people

more time for mutations to occur

how does cancer affect cell division

destroys the balance by decreasing death of damaged cells and increasing cell division

what are the intrinsic factors that cause cancer?

heredity, diet, and hormones

what are the extrinsic factors that cause cancer?

chemicals (e.g. smoking), infectious agents (HPV and H. Pylori), and Radiation

What are the 4 targets for DNA damage

1. growth promoting proto-oncogenes
2. growth inhibitory tumor suppressor genes
3. genes that regulate programmed cell death
4. genes that produce proteins involved in DNA damage and repair

what is apoptosis?

prorammed cell death

Oncogenes

genes that code for mutant forms of normal signalling molecules that regulate and control cell growth

what protiens do oncogenes alter?

1. growth factors
2. growth factor receptors
3.cytosolic transducers
4. nuclear transducers

what are tumor suppressor genes?

encode proteins that in their normal state negatively regulate proliferation

DNA damage repair (DDR) genes

code for proteins that correct/repair DNA mutations

in what three types of DDR defects contribute to cancers?

1. mismatch repair
2. nucleotide excision repair
3. recobination repair

defining features of a benign tumor

1. only grow locally
2. clear defined margins
3. dont metastasise

"What feature defines a tumor as ""Malignant"" without a doubt"

Mestasis unequvically marks a tumor as malignant because bengin neoplasms do not metastasise

what are metastases?

tumors that develop secondary to and discontinuous with the primary tumor

How do metastases travel around the body

via an artery, lymph vessel, or vein

Most common sites of cancer metastasis

brain, lymph nodes, respiratory, liver, skeletal

Leukaemia

cancer of the blood or bone marrow

Sarcomas

cancers of the connective or supportive tissues, and soft tissues

examples of connective or supportive tissues

bone, cartilage, fat, muscle, blood vessels

carcinomas

cancers of the epithelial cells

where can carcinomas arise?

breast, liver, lung, or GI tract

neoplasia

uncontrolled cell growth that follows no physiologic demand

neoplasm

new growth (tumor)

When is surgery indicated?

in early non-metastatic cancers and/or after radiotherapy and chemotherapy

Antineoplastic Agent

aim eliminate cancer cells without affecting normal tissues

What do most conventional chemotherapy drugs target

continuously proliferating cells

When does a cell arrest

when irreparable DNA damage is found

name a tumour suppressor gene

p53

name a cell cycle inhibitor

p21

what are the possible carcinogenic mechanisms of Oestrogen

gene transcription (promotes growth signals), second messengers (directly induces ERK, P13K, and EGFR), and metabolism (causing DNA damage)

Name the two oestrogen blocking treatments

Aromatase inhibitors, and tamoxifen

How do aromatase inhibitors work?

prevents conversion of androgens into oestrogen - tend to be used where tamoxifen fails

How does tamoxifen work?

binds to and blocks estrogen receptors

What are the three types of breast cancer?

ER-positive, HER2 positive, triple negative

what receptors doe ER-postivie breast cancer have?

Estrogen and/or progesterone

what receptors does HER2 postivie breast cancer have?

HER2 receptors

what receptors does triple negative breast cancer have

neither estrogen/progesterone or HER2

What are HER2 positive cancers treated with

Herceptin (Trastuzumab)

what are the MoA of herceptin?

antagonism of HER2 receptors, anti-body dependant cell mediate cytotoxicity, lysis of HER2-expressing cells

How is triple negative breast cancer treated?

chemotherapy if sensitive and surgery

What chemotherapy combinatin is used in triple negative breast cancer?

FEC-T (Fluorouracil, epirubicin, cyclophosphamide, docetaxel)

What requires monitoring in porstate cancer?

the prostate specific antigen (PSA)

what treatments are available for prostate cancer?

surgery, radiotherapy, chemotherapy, and androgen depravation therapy (ADT)

what is androgen depravation therapy (ADT)

inhibition of androgen synthesis

what factors does cancer treatment depend on?

"type of cancer ; progress of disease ; available options ; health of patient ; patient's preference"

What are the two ways cancer can be treated?

curatively and palliatively

What cells proliferate rapidly under normal circumstances?

bone marrow ; digestive tract ; hair follicles

What are the main side effects of chemotherapy?

myelosuppression ; mucositis ; alopecia

What is myelosuppression?

decrease in the production of blood cells and can lead to immunosuppression

what is mucositis?

inflammation of the digestive tract lining

what is alopecia?

hair loss

what is the problem with chemotherapies?

they are non-specific - attack health cells too

what factors can make cancer cells immune to some drugs?

decreased drug uptake/efflux ; enhanced tolerance of DNA adducts ; increased drug deactivation by intracellular glutatione ; toxicity to normal cells

What are the five major classes of chemotherapy drugs? (PlAnT-AlAn)

Platinates ; Anthracyclines ; Taxanes ; Alkylators ; Anti-metabolites

What is the mechanism of action of alkylating agents?

transfer of an alkyl group to the guanine base causing mis-paring of nucleotides leading to crossbridges which prevents DNA from being separated and therefore synthesis and transcription

What are the six groups of alkylating agents?

Nitrogen mustards ; ethylenimes ; alkylsulfonates ; triazenes ; piperazines ; nitrosureas

Name a nitrogen mustard.

cyclophosphamide ; melphalan ; carmustine ; chlorambucil

what is the mechanism of action for platinum based drugs?

alkylating like agents - they permenantly coodinate to DNA to interfere with the repair. (Cisplatin bends DNA at a 45 degree angle)

name the side effects of cisplatin

neurotoxicity ; nephrotoxicity ; nausea and vomiting ; myelotoxicity

name a paltinum based drug

cisplatin ; carboplatin ; satraplatin

what is the mechanism of action of anthracycline based drugs?

intercalating drugs cause local unwiding of hte double helix strucutre and causes base pairs to move apart. This iduces DNA breaks - interferes with toposimerase II which breask and reconects DNA strands

Name an anthracycline drug

doxorubicin ; daunorubicin ; epirubicin

what do patients on anthracyclines need monitored for?

myocardial toxicity - after cumulative doses between 450-500mg/m^2

what are the mechanisms of action of spindle poisons?

stabilise microtublues preventing normal breakdown (taxanes) ; bind to tublin monomers preventing microtubules from forming (vinca alkaloid)

name an example of a vinca alkaloid

vincristine

name an example of a taxane

paclitaxel (taxol) ; docetaxel

what are the two antimetabolite mechanisms of action

competative substrates - get incorporated into DNA instead of normal substrate ; enzyme inhibitors - inhibits enzymes involved in synthesis or uptake of substrate

what is the mechanism of action of purine analouges

antimetabolite as enzyme inhibitors - inhibit synthesis of guanine monophosphate

what is the mechanism of action of pyrimidine analogues?

antimetabolite as a competitive substrate - incorporated into DNA instead of dCTP preventing hte structure from elongation 

what is the mechanism of action of anti-folates?

antimetabolites as enzyme inhibitors - prevent reuptake and utilisation of folic acid (methotrexate inhibits the enzyme DHFR resposible for necessary metabolism of folic acid)

what is ionising radiation?

radiation that carries enough energy to free electrons

how does ionising radiation induce changes in cells?

by displacing electrons from their atomic nuclei - intracellular ionisation of molecules

how are free radicals produced within a cell?

free electrons hit water molecules producing a free radical

what is a direct effect of free electrons

free electrons directly hitting and damaging DNA

what is an indirect effect of free electrons in the cell?

free electron hits water molecule producing free radical which then reacts with and damages the DNA

what is the principal cause of chromosomal aberrations?

DNA double breaks

what is the aim of radiotherapy?

DNA double breaks

what is brachytherapy?

radioactive material placed inside the body near tumour cells

what are radiopharmaceuticals?

radioactive molecules injected into the blood stream

what does it mean when radiation is given in a conformational manner?

the radiation beam is manipulated to fit the tumours shape resultting in reduced tissue toxicity

what is interstitial brachytherapy?

radiation sources placed directly in the target tissue of affected site

what is contact brachytherapy?

radiation sources are placed in a space next to the target tissue

what are the acute phase side effects of irradiated tissues

1. acute mucosal inflammation
2. radiation dermitis
3. procedural pain - inserting brachytherapy

what are the late phase side effects of irradiated tissues

radiation fibrosis syndorme - accumulation of fibrin ; oesophageal stricture (narrowing) ; abdominal pain - bowel spasms ; non-bacterial cystitis ; strictures - bowel, anus, urethra

what cancer cells are radioresistant?

hypoxic cells - more defence mechanisms, upregulation of free-radical scavengers ; mutations ; cancer stem cells

how do radiosensitisers work

inhibition of repair ; down regulation of free radical scavengers 

what are the four different scans used in radio-diagnostics

PET scan ; MRI ; CT scan ; SPECT

what is theranostics

use of a radioactive drug for diagnosis and then therapeutic purposes

what is targeted radionuclide therapy?

delivery of radiation to a tumour using a delivery molecule with high affinity for only tumour cells with as low a dose to surrounding tissues as possible

what is radioimmunotherapy?

the use of an antibody to deliver radiotherapy to a target cell

what are the possible mechanisms of radioimmunotherapy?

self-killing - apoptosis ; complement-dependant cytotoxicity ; antibody dependant cytotoxicity ; ionsing radiation ; vaccine like effect

what is SACT

systemic anti-cancer therpy

what threatments does SACT refer to?

chemotherapy ; monocolonal antibodies ; immunotherapies ; cancer vaccines ; gene therapy

what does adjuvant mean

treatment given after another treatment - i.e. chemotherapy given to mop up any excess after surgey/radiotherapy

what does neo-adjuvant mean

treatment given before another - i.e. chemo given to shrink a tumour before going for surgery

what are the common toxicities in SACT

nausea/vomiting ; diarrhoea ; neuropathy ; dry mouth ; alopecia ; fatigue ; immunosuppression