Introduction to Cancer Chemotherapy Flashcards
What is cancer ?
This is when abnormal cell divide in an uncontrolled way
When cancers spread to other parts of the body, this is referred to as?
Metastasis
A primary tumour refers to…
a tumour (mass of abnormal cells) prior to metastasis and its ability to evade its tissue origins
A secondary tumor refers to…
a tumour that originates from a primary tumour that has metastasised
There are more than ____ types of cancer
200
What is the largest single preventable causes of cancer?
smoking
present in 15% of all cancer cases
What types of cancers account for over half (53%) of new cancers?
Breast
Prostate
Lung
Bowel cancers
Age is another risk factor for the development of cancer. What evidence is there to support this?
Over a third (36%) of all cancer cases in the UK are diagnosed in people aged 75 and over (2016-2018)
46% of oral cavity cancers in the UK are preventable, what lifestyle factors are linked to them?
smoking
betel quid
smokeless tobacco
alcohol
infections (HPV positive)
ionising radiation
sun exposure
certain occupational exposures- asbestos, inorganic acid mists, formaldehyde, wood dust, rubber
___ % of oral cavity cancers are in HPV positive patients
12%
The risk of oral cavity cancer is ___% higher in current smokers compared to never smokers
91%
What is the main avoidable risk factor of oral cancer?
smoking
What factors increase the risk of developing cancer?
Age
Genetics
Exposure to risk factors including avoidable lifestyle factors
What dietary inclusion has been found to be protective against oral cancer?
diet high in fruit and vegetables
insufficient fruit and vegetables are linked to an estimated 56% of oral cancer cases in the UK
What are the signs and symptoms of oral cancer?
sore mouth ulcers; do not heal within several weeks (80% of oral cancer patients)
unexplained, persistent lumps on the lip, mouth, throat and lymph glands of the neck
oral discomfort or pain that will not go away
persistent red or white patches on the lining of the mouth
difficulty when swallowing (dysphagia), chewing, moving jaw
feeling that something is caught in the throat
unusual bleeding or numbness in the mouth
loose teeth for no apparent reason or a tooth socket that does no heal
changes in voice and speech problems
unexplained weight loss
Halitosis
According to the NICE guidelines, when should a dentist consider a suspected cancer pathway referral (for an appointment within 2 weeks) ?
a lump on the lip or in the oral cavity consistent with oral cancer OR
a red or red and white patch in the oral cavity consistent with erythroplakia or erythroleukoplakia
How does an oral squamous cell carcinoma present on the lateral border of the tongue?
solitary ulcer with rolled border
How does an oral squamous cell carcinoma present on the ventral surface of the tongue and FoM?
as a red patch
How does an oral squamous cell carcinoma present on the buccal mucosa?
speckled patch
How does an oral squamous cell carcinoma present on the lower lip?
shallow ulcer
In cancer, the appearance of abnormal characteristic reflect altered patterns of gene expression in cancer cells, resulting from ________ or _________ mutations
Inherited
Acquired
Give an example of a cancer type with potential inherited mutations
Breast cancer
Give an example of a cancer type with acquired mutations
Oral cancer
What is the inherited mutation often implicated in breast cancer ? What is the function
BRCA1 and BRCA2
there are tumour suppressor genes
they are mutated and their tumour suppressor abilities are diminished; encouraging proliferation and discouraging apoptosis
What risk factors can contribute to the development of oral cancers ?
Exposure to viruses e.g. HPV, carcinogens (tobacco products, betel quid)
What is carcinogenesis?
This is the process by which normal cells are transformed into cancer cells
Carcinogenesis is a complex multi-stage process that involves…
more than one genetic change
What are the 2 main categories of genetic change in carcinogenesis?
Oncogenes (protoncogenes)
Tumour suppressor genes
What is the normal function of protoncogenes?
normally control cell division, apoptosis and differentiation
Activation of protoncogenes produces …
oncogenes
Give an example of a protoncogene
c-Myc gene
What is the normal function of tumour suppressor genes?
They slow down cell division, repair DNA mistakes and induce apoptosis
In cancer cells, TSGs are ____________.
inactivated
Give an example of a TSG
TP53
Mutated TP53 genes are found in ____% of tumours
> 50%
What is the effect of up-regulation of oncogenes and down-regulation of TSGs?
induction of malignant change
cells grow out of control
What is aneuploidy?
this is the presence of an abnormal number of chromosomes
What genetic changes can be observed in cancer cells?
chromosomal aneuploidiy
point mutations
deletions
duplications
amplifications
translocations
inversions
What is the karyotype of normal cells?
46 chromosomes
23 pairs
What are the 4 characteristics that cancer cells manifest than distinguish them from normal cells?
uncontrolled proliferation
de-differentiation and loss of function
invasiveness
metastasis
The production of what enzymes permits the invasion of nearby tissues by tumour cells?
metalloproteinases
_________ aids the support of metastasised tissue
Angiogenesis
Metastasis leads to the formation of ___________ tumours
secondary
What is de-differentiation ?
reversion to a more primitive version of the cell which can lead to a loss of function
Name the cellular systems that can be altered in cancer cells which cause uncontrolled proliferation
Growth factors
Cell cycle transducers
Resistance to apoptosis
Telomerase expression
Increase in which growth factor encourages angiogenesis?
VEGF
Vascular endothelial growth factor
Cell cycle transducers include …
cyclins, cyclin dependent kinases and CDK inhibitors
How are cancer cells able to resist apoptosis?
inactivation of pro-apoptotic factors
Activation of anti-apoptotic factors
What is the function of telomeres?
protect the genetic material and allow cell division
What happens to telomeres with continued cell division?
Gets shorter which can then cause senescence
What is the function of the telomerase enzyme?
to repair telomeres
Telomerase expression is ________ in cancer cells
increased
What are the stages of the cell cycle?
Interphase; G1, S, G2
Mitosis, cytokinesis (daughter cell formation)
What occurs at interphase?
growth of the cell
There is no division
What phase of the cell cycle are most normal cells at?
Interphase
What occurs in G1 phase of interphase?
growth of cell
cellular contents (organelles), excluding the chromosomes are duplicated
What occurs in the S phase of interphase?
duplication of chromosomes
23 pairs to 46 pairs
What occurs in the G2 phase of interphase?
cell double checks the duplicated chromosomes for any needed repairs
preparation for mitosis
What is the G0 phase of interphase ? What types of cells exist in this phase?
there is no cell division
neurones exist in this stage
What is mitosis?
this is where active cell division takes place
What are the classes of molecules that regulate the cells progression through the cell cycle?
Cyclins
Cyclin dependent kinases
What activates CDKs ?
cyclin molecules
Inactive CDKs are always present in the cell. True or false
True
Specific cyclins are made at specific times. True or false
True
What is the key checkpoint in the G1 phase of interphase. State the molecules involved an their effect.
cycD-CDK4 and cycE-CDK2
they phopshorylate and inactivate the Rb(retinoblastoma) protein which is a tumour suppressor. This in turn activates DNA synthesis
What is the key checkpoint in the G1 phase of interphase. State the molecules involved an their effect.
cycD-CDK4 and cycE-CDK2
they phopshorylate and inactivate the Rb(retinoblastoma) protein which is a tumour suppressor. This in turn activates DNA synthesis
What is the key checkpoint in the S phase of interphase. State the molecules involved an their effect.
cycA-CDK2
activates DNA replication
What is the key checkpoint in the M phase of interphase. State the molecules involved an their effect.
cycb-CDK1
activation of mitosis
What gene is referred to as the guardian of the genome?
p53
What is the function of p53 protein ?
p53 acts as a transcription factor and binds to DNA directly
Leads to downstream activation of p21 gene
What is the function of p21 protein?
complexes with CDK2 inhibiting it and prevents the cell from continuing onto cell division
What is the effect of a mutated p53 protein/gene on the cell cycle?
no p21 is produced to act as a stop signal for cell division
This leads to cancer
Mutated Rb protein/gene leads to…
retinoblastoma
Cancer treatment are specifically cytotoxic to what kinds of cells?
rapidly dividing cells
What is the general function of chemotherapy/anti-cancer drugs?
cytotoxic
most damage DNA and induce apoptosis
they are anti-proliferative
What are the side effects of chemotherapy?
depress bone marrow
impair healing (platelets)
depress growth
nausea and vomiting
sterility
hair loss
teratogenecity (malformation of foetus/embryo)
What is the mechanism of action of alkylating agents in cancer treatment ?
they form covalent bonds with DNA impeding DNA replication
They contain chemical groups that form covalent bonds with the nucleophilic groups in DNA
They form cabonium ion (cation)s which are attracted to nucleophilic group of DNA (mostly position N7 of guanine)
There are often 2 alkylating groups making it bifunctional
What is a nucleophile?
donates an electron pair for form a bond
What is the function of bifunctional alkylating agents?
they can cause intrastrand linking and crosslinking
Alkylating agents mainly have an impact on what phase of the cell cycle?
S phase
affects DNA replication
unpaired DNA is more susceptible
Where are nucleophilic groups of DNA mostly found ?
N7 position of guanine
What are the side effects of alkylating agents?
depress bone marrow function
cause hair loss
GI disturbances
increased risk of acute non-lymphocytic anaemia (fast growing myeloblasts)
What is the effect of prolonged use of alkylating agents?
gametogenesis
Sterility particularly in men
Give examples of alkylating agents
nitrogen mustards
nitrosoureas
platinum compounds
other
Give an example of a nitrogen mustard
cyclophsophamide
What are some side effects of cyclophosphamide?
nausea and vomiting
bone marrow depression
haemorrhagic cystitis (lining of bladder becomes inflammed and starts to bleed)
immunosuppressant (affects lymphocytes)
Cyclophopshamide is a prodrug which is converted in the liver by ______
P450 enzymes
Give examples of nitrosoureas
Lomustine
Carmustine
What are the side effect of nitrosureas?
severe bone marrow depression
Nitrosoureas can be used to treat brain tumours because…
they are lipid soluble and thus can cross the BBB
What are side effects of other alkylating agents such as decarbazine ?
myelotoxicity
severe nausea and vomiting
Decarbazine is a prodrug and is activated in the liver by P450. True or false
True
How do platinum compounds differ from other alkylating agents?
they do not have carbonium ions
they have ethylene ammonium (lose chloride ions)
Ethylene ammonium is unstable
Give an example of a platinum compound
cisplatin
What are the side effects of platinum compounds?
severe nephrotoxicty
severe nausea and vomiting
peripheral neuropathies
ototoxicity (hearing or balance problems due to medication)
Platinum compounds are revolutionised for treating what kinds of tumours?
revolutionised treatment of germ cell tumors
What is the MOA of antimetabolites ?
they disrupt the metabolic pathways involved in DNA synthesis
disruption of nucleotide bases?
What is the MOA of methotrexate?
Methotrexate inhibits the action of DHFR (dihydrofolate reductase) enzyme
methotrexate is an antagonist of folate (prevents formation of FH4) therefore interfering with the action of thymidylate synthetase
Briefly state how dTTP (pyrimidine base- thymidine) is formed
DHFR reduces folates to tetrahydrofolate (FH4)
FH4 acts as a co-factor (methyl group donor) necessary for the conversion of dUMP to dTM by the enzyme thymidylate synthase (TS)
dTMP can then be phosphorylated to form the pyrimidine base dTTP (thymidine) which is required for DNA synthesis
What is the MOA of fluorouracil?
Inhibits the action of thymidylate synthetase (prevents production of dTMP from dUMP)
it is a pyrimidine (thymine, uracil, cytosine) analogue; a fraudulent nucleotide which binds to and inhibits thymidylate synthase
How is methotrexate resistance developed?
pumps on the cell surface can pump out methotrexate
Methotrexate can also be used as an ______________ drug?
immunosuppresant
What are the side effects of methotrexate?
bone marrow depression
damage to GI tract epithelium
pneumonitis
nephrotoxicity (high doses)
What are the side effects of fluorouracil?
damage to GI tract epithelium
myelotoxicity
Give an example of a purine analogue ? What is their function
Mercaptopurine
they can disrupt other pathways involved in DNA synthesis
What is the mechanism of action of cytotoxic antibiotics?
they often have direct action on DNA
What is the function of the topisomerase enzyme?
encourages DNA unwinding
prevents DNA tangling by cutting through one strands of the DNA molecule
The unbroken strand then goes through the broken strand thus untangling the protein molecule.
What is doxorubicin?
an anthracycline antibiotic derived from the streptomyces bacterium
What is the MOA of doxorubicin?
they bind to DNA and inhibit DNA and RNA synthesis
They do this by stabilising the topoisomerase II-DNA complexes that are easily cleaved or it interferes with its catalytic activity
this results in double stranded breaks in DNA (easily cleaved state)
this causes arrest in the cell cycle at the G2 phase
What are the side effects of cytotoxic antibiotics
myelosuppression
hair loss
cardiotoxic in high doses
nausea and vomiting
What is the relevance of the plant derivative (mandrake root) Etoposide in cancer therapy?
it is thought to an an effect on topoismerase II similar to doxorubicin although this remains unclear
Give examples of hormone sensitive tissues
Breast
Uterus
Prostrate
What is the rationale for the use of hormone antagonists in cancer therapy ?
tumours that arise in hormone sensitive tissues may be hormone dependent due to the presence of hormone receptors on these malignant cells
Their growth ca therefore be inhibited by hormone antagonists or the inhibition of hormone synthesis
What is the MOA of tamoxifen?
an anti-oestrogen; oestrogen antagonist
it competes with endogenous oestrogen for the oestrogen receptors inhibiting the transcription of oestrogen responsive genes
What is the MOA of anastrozole?
it is an aromatase inhibitor
oestrogen is synthesised from androgens in the adrenal cortex, either immediately (androstenedione) or through testosterone both catalysed by the enzyme aromatase
What kind of cancer is anastrozole used to treat?
Post-menopausal breast cancer
Anastrozole inhibits aromatase, suppressing oestrogen synthesis
What are the common side effects of tamoxifen (competitive oestrogen antagonist)?
light headed
hot flushes and sweats
nausea and vomiting
tiredness or fatigue
irregular periods
hair thinning
What are the rare side effects of tamoxifen?
Tumor flare (bone pain, if cancer has spread there)
skin rash
liver changes
risk of blood clots (thrombosis)
increased risk of developing womb cancer
What are the common side effects of anastrozole?
headaches
hot flushes and sweats
nausea and vomiting
tiredness or fatigue
mood changes
skin rashes
What are the rare side effects of anastrozole?
tumour flare- bone pain if the tumour has spread there
hair thinning
liver changes
diarrhoea
vaginal bleeding
What is the rationale for the use of monoclonal antibodies and protein kinase inhibitors in cancer therapy?
many tumours overexpress growth factors, stimulating cell proliferation and tumour growth
What is the MOA of monoclonal antibodies?
they bind to growth factor receptors or bind to and neutralise growth factors
Give examples of monoclonal antibodies that bind to growth factor receptors?
Transtuzumab
Cetuximab
Give examples of monoclonal antibodies that bind to and neutralise growth factors?
bevacizumab
What is the function of imatinib?
monoclonal antibody that prevents downstream signalling triggered by growth factors by inhibiting specific oncogenic kinases
List some side effects of trastuzumab
Anaemia
Alopecia
constipation
dry eyes
cystitis (inflammation and bleeding of the bladder)
hypersensitivity
List some side effects of cetuximab
decreased appetite
hypersensitivity
nausea
eye inflammation
interstitial lung disease
List some side effects of bevacizumab
abscess
anaemia
constipation
hypersensitivity
arthalagia
vomiting
Lis some side effects of imatinib
dysphagia
drowsiness
dizziness
anxiety
arrhythmias
What is primary resistance to cytotoxic drugs?
resistance that is present when the drug is first administered
What is acquired resistance to cytotoxic drugs ?
resistance that is through adaptation or mutations during drug treatment
What is the mechanism for resistance to doxorubicin?
decreased accumulation of cytotoxic drug; increased expression of cell surface pumps
What is the mechanism for resistance to methotrexate?
a decrease in the amount of drug taken up
What is the mechanism for resistance to fluorouracil, mercaptopurine?
insufficient activation of the drug
What is the mechanism for resistance to mercaptouring?
increase in inactivation
What is the mechanism for resistance to methotrexate?
increase the concentration of the target enzyme
DHFR- dihydrofolate reductase
What is the mechanism for resistance to antimetabolites?
increased utilisation of other metabolic pathways
What is the mechanism for resistance to alkylating agents
rapid repair of drug induced DNA damage
What is the mechanism for resistance to doxirubicin?
altered activity of the target (topoisomerase II)
What is the mechanism for resistance to P53 agents?
mutation of various other genes
What are some oral complications related to chemo and radiotherapy?
oral bleeding due to bone marrow effects
oral mucositis (inflammation of mucosa)
infection
salivary gland dysfunction
dental decay
changes in perception of food
abnormal dental development (children)
osteonecrosis
poor nutrition
functional disabilities
neurotoxicity
What is the implication of increased risk of bleeding and infections due to cancer therapy in dental treatment?
surgical procedures such as extractions should be avoided
What is the implication of drug to drug interactions with cancer therapy?
consult BNF or discuss with patients oncologist if there is any doubt about prescribing another medication
