Cancer Treatment Flashcards
what are some drugs of alkylating agents and nitrosureas?
ifosfamide, cyclophosphamide, melphalan, chlorambucil, cisplatin, carmustine
what is the MOA of alkylating agents and nitrosureas?
addition of an alkyl group to nucleic acids/proteins/DNA
= inhibition of DNA replication = increase mutations (=secondary cancer) or cell death
any time of cell cycle
what are the main side effects of alkylating agents and nitrosureas?
teratogenic and carcinogenic
name sub classes of alkylating agents
a) Nitrogen mustards
b) Alkyl sulfonates (e.g. busulfan)
c) Triazines (e.g. dacarbazine, temozolomide)
d) Nitrosoureas (e.g. carmustine, lomustine)
e) Metal salts
what is mechlorethamine?
also known as Mustine
rarely used
short half life
very corrosive = toxic
tissue damage
nausea and vomiting side effects
what is melphalan?
oral given for myeloma - cancer of plasma cells
IV conditioning pre-transplant
increased risk of myelodysplasia with prolonged use
what is Cyclophosphamide?
A type of chemotherapy
activated in the liver, and broken down into into acrolein and etc.
what is acrolein?
bladder irritant
risk of haemarradic cystitis
what is the antidote for acrolein? and how?
MESNA
mops up the acrolein
what is bendamustine?
licenced for CLL and NHL
what are metal salts?
cisplatin, carboplatin and oxaliplatin
inhibit DNA synthesis via inter/intra- strand cross links mainly binding to GUANINE
whats cisplatin’s half life?
long half life
60 hours
what are side effects of metal salts?
nephrotoxic
neurotoxic - nause/vomiting
what are antimetabolites?
exert cytotoxic effects to natural metabolites involved in nucleic acid synthesis
The cell mistakes them for a normal metabolites, resulting in:
- inhibition of critical enzymes involved in nucleic acid
synthesis
- incorporation into the nucleic acid, leading to incorrect codes
LARGELY S-PHASE SPECIFIC
examples of anti-metabolites?
folate antagonists
pyrimidine analogues
purine analogues
ribonucleotide reductase inhibitors
MOA of 5-FU drugs
is a pyrimidine analogue that can be misincorporated into RNA and DNA in place of uracil or thymine
what is DHFR?
reduction enzyme
dihydrofolate reductase responsible for folates to be reduced to tetrahydrofolate -responsible for thymidine and purine synthesis
what is folate antagonists?
competitively inhibit DHFR= inhibit thymidine and purine synthesis
name some examples of folate antagonsists?
MTX
pemetrexed
raltitrexed
what is MTX?
inhibit dihydrofolate reductase (DHFR), leading to inhibition of DNA and RNA synthesis.
renally cleared- largely unchanged
half life- 8-10hrs may accumulate to 24-36hrs
when is folic acid prescribed w MTX?
alternate days to MTX dose
one per day or once a week
why can folic acid not be co-prescibed with MTX?
MTX 100,000x affinity for enzyme than folic acid
Folic acid may interfere with the gastrointestinal absorption of methotrexate.
what can large amounts of DHFR cause?
mtx resistance
how can mtx resistance be overcome
increase mtx dose
why is folic acid prescribed w mtx?
for treatment/rescue to healthy cells = reduce toxicity to healthy cells = decrease side effects
mtx side effects
myelosuppresion
mucositis
renal toxicity
alkalisation of urine and vigorous hydration alongside mtx administration
why do we monitor urine pH w MTX?
acidity of urine due to MTX crystallisation which can cause kidney damage
to alkalise using sodium bicarb
mtx drug interactions
aspirin/ciprofloxacin/NSAIDs = reduce tubular secretion of MTX due to renal tubular competition = increase toxicity
what is leucovorin/folinic acid?
form of THF
maintain normal cell functions - reverses MTX toxicity
when will leucovorin/folinic acid be given?
mucositis and myelsuppression
what is mucositis?
when your mouth or gut is sore and inflamed
what is pyrimidine analogues?
fraudulent nucleotides - cytosine, thymine and uracil
examples of pyrimidine analogues?
5-fluorouracil (5-FU),
gemcitabine,
capecitabine - erratic oral absorption
what is 5-FU?
a pyrimidine analogue
activated to 5-F-dUMP= inhibits thymidylate synthase =
inhibits RNA SYNTHESIS
15mins half life - therefore prolonged infusions/bolus needed
eratic oral absorption
colorectal/breast/stomach/oesophagus/head/neck carcinomas
how can we stabilise 5-F-dUMP?
co-administer folinic acid = enhances activity
what is capecitabine?
oral 5-FU drug
prodrug
conversions to 5-FU within the liver and tumour cells
breast/gastric/pancreatic cancer
is capecitabine or 5-FU better?
capecitabine better tolerated more
but experience more hand and foot syndrome
what is Gemcitabine?
Converted to gemcitabine triphosphate which is incorporated into DNA in place of deoxycytidine triphosphate.
- Given weekly.
- Licensed for pancreatic cancer, non-small cell lung cancer, bladder
cancer and breast cancer.
what is Cytarabine?
Converted to active form, ara-CTP which inhibits DNA polymerase.
- May also be directly incorporated into DNA chain, preventing replication and making it more susceptible to degradation.
- Most useful in tumours with high growth fraction, and mainly used for AML, ALL and certain lymphomas.
what is purine analogues?
Can be incorporated into the growing DNA chain in place of the natural nucleotides adenine & guanine
* Can also inhibit the enzymes involved
* May kill cells, including cancer cells
give examples of purine analogues?
6-mercaptopurine, 6-thioguanine, fludarabine
what is 6-mercaptopurine?
prodrug - oral
inhibits various metabolic reactions including purine biosynthesis
azathioprine
what is fludarabine?
The active triphosphate, 2F-ara-ATP inhibits a variety of enzymes involved in DNA synthesis
ORAL
what is an example of rinbonucleotide reductase inhibitor?
hydroxycarbamide
what is the MOA of hydroxycarbamide?
Inhibitor of ribonucleotide reductase, an enzyme essential for the generation of deoxyribonucleotides
* Prevents purines and pyrimidines synthesis= decrease DNA conc.
* May also damage DNA = inhibit DNA repair.
* Used in haematological malignancies – CML, polycythaemia,
thrombocythaemia
* Given orally as 500mg capsules – dose tailored to response
what are the antimetabolites MOA?
- folate antagonists
- inhibit the action of folates which are co-factors essential for nucleotide synthesis - pyrimidine analogues
- mimic/inhibit synthesis of cytosine, thymine & uracil thereby
interfering with DNA synthesis - purine analogues
- mimic/inhibit synthesis of adenine & guanine interfering with DNA synthesis - ribonucleotide reductase inhibitors
what are the classes of mitotic inhibitors?
vinca alkaloids -vincristine
taxanes
moa of mitotic inhibitors
act on microtubules in the nucleus = arresting metaphase = inhibit mitosis
what are examples of vinca alkaloids?
vincristine, vinblastine,
vindesine, vinorelbine
what is the MOA of vinca alkaloids?
bind to tubulin = prevent microtubule assembly
what is vincristine?
used in haematology,
indication - sarcoma and neuroblastoma
can cause neurotoxicity n mild myelosuppression
metabolised in the liver and excreted in faeces via cyto P450
what are examples of taxanes?
paclitaxel
docetaxel
abraxane
cabazitaxel
explain taxanes/ paclitaxel
indication - ovarian /breast cancer
stabilisers of microtubule
poor water solubility
risk of hypersensitivity reactions, neutropenia , neurotoxicity, alopecia, cardiotoxicity
what are Topoisomerase inhibitors?
nuclear enzymes that cause DNA strand breaks and therefore allow it to unwind during cell division.
Inhibitors stabilise the enzyme-DNA complex and prevent re-ligation, resulting in irreversible DNA strand breaks.
S/G2 phase of the cell cycle
- Topoisomerase I - causes single nick in DNA
- Topoisomerase II - cleaves both strands
what are the types of Topoisomerase inhibitors?
- Topoisomerase I - causes single nick in DNA
- Topoisomerase II - cleaves both strands
what can inhibit topoisomerase II?
etoposide
indications of etoposide?
oral/iv
small cell lung cancer/ testicular cancer /lymphoma
what are some example of topoisomerase I ?
topotecan
irinotecan
what are some antitumour antibiotics?
- anthracyclines
- inhibition of topoisomerase II
- DNA intercalation
- free radical formation
- alkylation
- Examples include:
- doxorubicin, daunorubicin
- idarubicin, epirubicin
- mitoxantrone
- actinomycin D
- mitomycin C
- bleomycin
what is mitoxantrone?
Structurally related to anthracyclines
* Does not produce free radicals so less cardiotoxic
* Indications include AML, breast cancer, prostate cancer.
what is actinomycin D?
Binds to DNA and inhibits DNA-dependent RNA synthesis. Also inhibits topoisomerase II.
* Used for sarcomas.
what is mitomycin C?
Causes cross-links between complementary DNA strands, which inhibits replication.
Commonly used for lung cancer. Also given intravesically for bladder cancer.
Causes delayed myelosuppression.
what is bleomycin?
Causes DNA strand scission - resulting in fragmentation of DNA.
Indications include testicular cancer, Hodgkin’s and NHL.
Risk of cumulative pulmonary toxicity.
why are biologics used in cancer treatment ?
using understanding of biology of the tumour and TME to control the disease
e.g. allowing switching of cytokines relative to the TME
what is rituximab like as a biologic ?
more targeted biologic - monoclonal antibody
targets antigens expressed on the cancer cell
what is thalidomide like as a biologic ?
non specific biologic
modulates the immune system
what is the main treatment of chronic myeloid leukaemia (CML)?
allogenic SCT - stem cell treatment
given with a large amount of chemo therapy
this allows the immune system to be restored
what are the types of cytokines?
Interleukin-2
* Produced by activated T-cells.
* Stimulates T-cell proliferation and activates NK cells.
* Has been used in renal cell cancer and melanoma.
Interferon-alpha
* Possesses a variety of immunomodulatory effects
e.g. activation of NK cells modulation of antibody production inducing antigen presentation on tumour cells
what is an example of an immunomodulator?
thalidomide
what indication is interferon-alpha used for?
renal cell
carcinoma
describe thalidomide use in cancer?
inhibit angiogenesis = prevent tumour spread
immunodulation too ! alters immune response
how are monoclonal antibodies used in cancer treatment?
Binding to tumour-associated antigens
Destruction of the tumour cell by blocking the growth and spread of cancer cells by interfering with cellular functions necessary for their survival.
when are checkpoint blockade used in cancer treatment?
used in haematology and oncology
what are some examples of checkpoint blockades in cancer treatment?
Pembrolizumab and nivolumab inhibit PD-1 and have multiple indications – melanoma, lung, bladder, renal cell, head and neck , Hodgkin lymphoma
Atezolizumab is a PD-L1 inhibitor – used for bladder and lung
Ipilumumab – inhibits CTLA-4 and is used to treat advanced
melanoma
OPPOSITE
Abatacept – enhances CTLA-4 and can be used for RA, kidney transplant rejection
describe Ipilimumab
antibody binds to CTLA4 on a T cell = activate T cell by blocking B7 + CTLA4 process (= inactivate T cell)
describe nivolumab/pembrolizumab
blocks overexpressed PDL1 and blocks PD1 on cancer cells = T cell activation
PDL1+PD1 binding = T cell inactivation
describe rituximab
A monoclonal antibody, specific for CD20, expressed on the surface of mature B cells.
* After binding Rituximab causes cell death by:
- induction of apoptosis
- activation of patient’s immune system
- sensitisation of resistant lymphoma cells to conventional chemotherapy
what are the ways rituximab induces cell death?
- induction of apoptosis
- activation of patient’s immune system
- sensitisation of resistant lymphoma cells to conventional chemotherapy
what are the side effects of rituximab?
infusion related
e.g. fever/chills/rigors
RARE: cytokine release syndrome - can be fatal
why do you get fevers/chills/rigors from taking rituximab?
due to foreign substances/antibodies inducing an immune response
how do you prevent rituximab from getting side effects?
pre-medicate with antihistamine/paracetamol/steroids
or slow down the infusion rate
describe trastuzumab/ HERCEPTIN
antibody against HER2 antigen which is over-expressed in some breast cancer cells
monotherapy or in combo
what occurs between trastuzumab/ HERCEPTIN and doxorubicin?
concerns of cardiac toxicity
describe alemtuzumab
antibody against CD-52, against specific lymphocytes
used for T cell depletion prior to allogenic BMT
used for Chronic Lymphocytic Leukaemia (CLL) and Multiple sclerosis
describe how T cell cancer therapy to kill tumour cells
- blood drawn from the pt and T cells are separated out
- t cells are genetically engineered to produce surface receptors called Cars
- Cars recognised and attaches to specific proteins on tumour cells
- cars T cells multiply while the pt has chemotherapy to kill off existing t cells
- transfer t cells into the body to recognise and kill cancerous cells
what does Cars do?
produced from genetically engineered T cells
target CD19 on B cells
Cars recognised and attaches to specific proteins on tumour cells
when are CARS used?
treat advanced B-ALL, advanced non-hodgkin lymphoma and mantle cell lymphoma
whats a risk of CARS?
cytokine release syndrome and neurological complications
what are the symptoms of cytokine release syndrome
fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing
what are the subtypes of targeted therapies?
- proteasome inhibitors
- protein kinase inhibitors/nibs
- PARP inhibitors
- BCL-2 inhibitors
- Hedgehog pathway inhibitors
- VEGF inhibitors
describe proteasomes
key roll in cellular degradation - accumulation of proteins = toxic to cells
what are proteasome inhibitors used to treat?
multiple myeloma
what is bortezomib ?
a proteasome inhibitor
IV bolus inf. and SC
describe the side effects of bortezomib
neuropathy
thrombocytopenia
fatigue
describe the side effects of proteasome inhibitors
neuropathy
thrombocytopenia
fatigue
name some proteaome inhibitors
bortezomib -iv inf/sc
carfilzomib -iv inf
ixazomib -oral
describe protein kinase inhibitors/nibs
target growth factors on receptors of cancer cells
oral therapies
given continuously
give an example of nibs
imatinib
FLT-3 inhibitors
what is imatinib used for
CML used for BCR-ABL
BCR-ABL kinase selective inhibitor
what are the common side effects of imatinib
haematological toxicities
diarrhoea
rash
oedema
nausea
cramps
headache
what are some drug interactions of imatinib
itraconazole, clarithromycin, phenytoin, rifampicin, warfarin, ciclosporin
what are FLT-3 inhibitors
FLT3 mutations occur im AML
inhibits mutations properties:
cellular growth
anti-apoptotic signalling
cellular survival
what are PARPi used for?
ovarian and breast cancer
what are some examples of PARPi
olaparib, niraparib, rucaparib - ovarian cancer
olaparib, talazoparib - breast cancer
describe PARPi
inhibit PARP enzymes used for DNA repair of cancerous cells = cell death
generally require BRCA mutation to cause cell death
describe BCL-2 inhibitors
inhibit BCL-2 = overexpressed in many cancers e.g. CLL
BCL-2 inhibits BAX/BID/BAK= inhibit cyto c release from mitochondria = no caspase enzymes released = no cellular apoptosis
what is an example of BCL-2 inhibitor?
venetoclax
what is venetoclax?
BCL-2 inhibitor
used for CLL and AML and others. - lymphoma/myeloma
what are the side effects of venetoclax?
tumour lysis syndrome (TLS) so start with a low dose and titrate up
why is a lower dose of venetoclax given in AML
as venetoclax is given with posaconazole = increases venetoclax conc. systemically therefore we can give a lower dose to give a similar efficacy of venetoclax
without risk of TLS
describe VEGF inhibitors
inhibit VEGF = inhibit angiogenesis = prevent tumour growth and spread
VEGF = promotes angiogenesis
what are some examples of VEGF inhibitors
- MABs e.g. bevacizumab, ramucirumab
– TKIs e.g. sunitinib, axitinib. Commonly for kidney cancer
– Aflibercept (a modified antibody)
when should you take etoposide capsules?
before food
when should you take uftoral capsules?
before food
when should you take capecitabine tablets?
with/after food
which cancer drugs can cross the BBB
small lipophilic drugs :
MTX
cytarabine
BCNU
when do you need to be careful when prescribing hydrophilic drugs?
and example
overdosing in obese pts
e.g. doxorubicin
why are the people with liver disease at higher risk when taking drugs?
poor drug metabolism due to a lack of cyto P450 = risk of toxicity
what drugs need dose reductions in renal impairment?
cisplatin
carboplatin
MTX
etoposide
bleomycin
what drugs are nephrotoxic? and how can you reduce effects?
cisplatin - requires adequate hydration
MTX - alkalise urine in high doses
what drugs need dose reductions in hepatic impairment?
doxorubicin
vincristine
paclitaxel
etoposide
what drugs are hepatotoxic?
nitrosureas - elevated liver enzymes
MTX - fibrosis/cirrhosis
what factors determine success of chemotherapy?
objective of treatment
pt factors
factors related to the tumour
what may be the overall objective of chemo treatment?
- attempt to cure disease
- focus on symptom palliation
- choice of adjuvant chemo
what are pt factors that effect chemo success?
medical condition
age
motivation
psychological status
what are tumour factors that effect chemo success?
sensitivity to chemo
clinical stage/size
growth characteristics
what are the effects of chemotherapy on various cancers?
- Often curative:
ALL and AML, especially in children
Testicular cancer
Hodgkin and non-Hodgkin lymphoma Wilms’ tumour - More than 30% responsive
Breast cancer
Small cell lung cancer
Multiple myeloma
CLL - Usually highly resistant
Non-small cell lung cancer
Renal cell carcinoma
Pancreatic cancer
what is adjuvant chemotherapy?
chemo/radiotherapy given after surgery
eradicate micrometastases
low toxicity regimen
what is neo-adjuvant chemotherapy?
chemo/radiotherapy given before surgery
what is the advantage of neo-adjuvant chemotherapy?
- Earlier exposure to cytotoxic drugs
- Can measure objective response in primary lesion - helps determine likely success or failure of chemo.
- Regression of the primary tumour may allow for less extensive surgery.
what is the disadvantage of neo-adjuvant chemotherapy?
- increased thrombocytopenia
- if chemo is not a success the tumour size can grow = increase surgery risk
how are combination chemotherapy drug treatments prescribed?
Basic principles
1. Choose individually active drugs
2. Choose drugs with non-overlapping toxicities
3. Choose agents with different modes of action
4. Choose agents that do not display cross-resistance
5. Use drugs at their optimal dose and schedule
6. Treatment-free interval should be the shortest possible to allow recovery of most sensitive host tissue
why are combination chemotherapy used?
Combinations usually more successful than single agent chemotherapy.
- prevention of resistant clones
- cytotoxicity to resting and dividing cells
- biochemical enhancement of effect
name phase specific drugs
S PHASE
- cytarabine
- MTX
- 5-FU
G2 PHASE
- bleomycin
- etoposide
M PHASE
- vinca alkaloids
- paclitaxel
name whole cell cycle specific drugs
Alkylating agents - chlorambucil, cyclophosphamide, cisplatin
Antibiotics - doxorubicin, epirubicin
name cell cycle non-specific drugs
Nitrogen mustard
Nitrosureas - carmustine, lomustine
what is BEP?
combination regimen for testicular cancer
BLEOMYCIN + ETOPOSIDE + CISPLATIN
describe bleomycin
inhibits DNA synthesis
G2 phase
what are side effects of bleomycin?
- toxic to skin and mucous membranes
- can cause pulmonary toxicity
what are side effects of etoposide?
- myelosuppressive, usually alopecia
- moderate nausea and vomiting
- given slowly to avoid hypotension
what are side effects of cisplatin?
- nephrotoxicity, ototoxicity, neuropathy - severe nausea and vomiting
