5.1 Cancer Chemotherapy Flashcards
What is the trade name of Imatindib and what is its target?
STI571 - Glivec ➡ “magic bullet”
It targets the Bcr-Abl tyrosine kinase inhibitor (mutation seen in children with CML)
Give 3 benefits of Imatinib
- Tumour selective
- More efficacious than other drugs
- Fewer side effects
Describe the Structure of DNA (4)
- Nucleotide = sugar phosphate-base
- DNA = double helix of nucleotides
- Purines = Adenine and Guanine
- Pyridimines = Cytosine and Thymine (Uracil in RNA)
In the body which 2 sites have the fastest cell turnover?
What is the implication of this for cancer growth
The gut and the bone marrow
Fast cancer growth meaning diagnosis often occurs during late stage/ after metastisis
Why is chemo treatment given every 21 days?
To achieve best possible selectivity
This will continue targeting/damaging cancerous cells BUT allow the normal healthy cells to recover
What is the ‘fractional cell kill hypothesis’
states that a defined chemotherapy concentration, applied for a defined time period, will kill a constant fraction of the cells in a population, independent of the absolute number of cells.
What are the 3 classifications of tumours according to chemo-sensitivity
Highly Sensitive
Modest Sensitivity
Low Sensitivity
Give an example of 2 tumours which are highly sensitive to chemo
- Lymphomas
- Germ cell tumours
- Small cell lung
- Neuroblastoma
- Wilm’s tumour
Give an example of 2 tumours which are moderately sensitive to chemo
- Breast
- Colorectal
- Bladder
- Ovary
- Cervix
Give 2 tumours which have low sensitivity to chemo
- Prostate
- Renal cell
- Brain tumours
- Endometrial
Give 4 drug classes which target tumours at a cellular level and state where each acts
Alkylating agents: DNA itself
Antimetabolites: DNA synthesis
Intercalating agents: DNA transcription and translation
Spindle poisons: Mitosis
At what 2 phases of the cell cycle are alkylating agents most effective
Max effect during ‘S’ phase due to greastest replication + large numbers of unpaired strands
OR
G1 when DNA synthesis enzymes are being transcribed. Disruption here will reduce number of enzymes, thus interfering with the process of cell division
What drug class are Platinum Compounds part of and give their MoA
Alkylating agents ➞ directly modify DNA structure
Undergo chemical reactions with DNA to form platinated inter-strand and intra-strand adducts.
This interferes with DNA replication and RNA transcription ➞ inhibits DNA synthesis
(Inhibition of replication = main cause of cell death)
What are the 2 most common platinum intra-strand adducts?
55% G-G and 30% A-G adducts
(with intra-stand linking being most favoured)
What are DACH platinum adducts, and how do they differ from platinum adducts?
DACH = diaminocyclohexane
DACH platinum adducts are bulky and thought to be more effective in inhibiting DNA synthesis than platinum adducts
Give the MoA of antimetabolites
Antimetabolites are structurally related to precursors involved in DNA synthesis.
They act to interfere with the production of the purine or pyearimidine nucleotides by acting as a direct competitive analogue in DNA or RNA synthesis
Give 2 examples of Antimetabolites and what each targets
1) Methotrexate: potent inhibitor of Dihydrofolate Reductase (DHFR) which interferes with folate metabolism
2) 5-Fluorouracil: pyearimidine analogue of the base uracil
Give the MoA of 5-Fluorouracil
5-FU is activly transported into the cell through the same mechanism as uracil (uracil analogue)
5-FU is converted into 5-FdUMP (active form of drug), which competes with dUMP for a binding site on Thymidylate Synthase.
Once bound 5-FdUMP combines with a co-enzyme to produce a stable complex that is irreversible. This complex inhibits the enzyme causing ‘thymidine-less cell death’
What is folate necessary for?
Folates are vital for production of purine and thymidilate nucleotides which enables DNA and RNA synthesis.
How is Folate metabolised?
Folate is activly taken into cell and converted in to a polyglutamate. The polyglutamated folate is reduced in two steps by DHFR to produce a tetradyhdrofolate
This then acts as a co-factor to covert DUMP into DTMP by the Thymidylate Synthase enzyme.
DTMP contributes to the production of the purines and pyearimidines required for DNA and RNA synthesis
Give the MoA of Methotrexate
Methotrexate is structurally similar to folic acid. It is actively transported into the cell and polyglutamated
Methotrexate alone has a much higher affinity than folate for DHFR. The polyglutamated form also has a very long half-life within the cell and high affinity for DHFR
Both Methotrexate alone and its polyglutamated form act to reduce the metabolism of folate which reduces nucleotide production (mainly thymidine)
During what phase of the cell cycle are anti-metabolites most effective?
In which case would therefore be least effective?
Most effective during the ‘S’ phase: period of maximal DNA synthesis
They have less effect during the resting state hence are not indicated for use in low growth malignancies
Describe the structure of microtubules
Protein subunits, α and β tubulin
How does spindle formation occur during DNA replication
1) chromosome align at the metaphase plate
2) spindle microtubules depolymerize, moving sister chromatids toward opposite poles
3) nuclear membrane re-forms and cytoplasm divides
What are the 2 targets of microtubule-binding agents
1) Inhibit polymerisation
2) Stimulate polymerisation and prevent depolymerisation
Give 2 types of spindle poisons/ microtubule inhibitors and what each targets
1) Vinca alkaloids: inhibit polymerisation of tubulin
2) Taxanes: promote and stabilise formation of tubulin polymer into microtubules
Give 2 examples of Vinca alkaloids
vincristine and vinblastin
Give the MoA of Vinca alkaloids
Bind to the β-tubulin subunit inhibiting formation of the microfilaments that make up the microtubule
Results in inabiliy for mitotic spindle to form and the cell cycle is halted in metaphase. Chromosomes cannot separate and affected cells cannot proliferate
Leads to apoptotic cell death
Give an example of a Taxane
paclitaxel
Give the MoA of Taxanes
Taxanes reversibly bind on the β tubulin subunit (at a different site to that of vinca alkaloids)
Binding stabilises the microtubules and inhibits their disassembly. This results in microtubules rendered non-functional as they cannot disassemble to pull the chromosome apart
The cell cycle remains stuck in metaphase which triggers apoptotic cell death in both cancer cells and normal cells
Is the aim of chemotherapy the same for all cancers?
NO aim is very different in different malignancies
The ‘predicted response’ of chemo differs within the same cance type, what 4 things is this based on?
1) performance score
2) clinical stage
3) prognostic factors or score (often involving biological factors)
4) molecular or cytogenetic markers
What must we consider before giving chemotherapy?
Side effects vs anticipated or best outcome
What are the 2 broad chemotherapy regimens?
Which is more commonly given and why?
1) a single drug
2) combination chemotherapy (number of different drugs)
Combination is more common because it reduces the chances of cell resistance
Give 4 routes of administration for chemotherapy
IV = most common
What are the 2 types of IV pumps?
1) PICC Line
2) Hickman Line
Give 4 side effects of chemotherapy
What are the adverse effects of chemotherapy due to?
The effect of treatment on the tumour
Give 3 adverse effects of chemotherapy (systemic effects)
(Incl why and/or type of cancer commonly involved)
1) Acute renal failure (multifactorial) ➞ rapid tumour lysis leads to precipitation of urate crystals in renal tubules causing hyperuricaemia
2) GI perforation at site of tumour (reported in lymphoma)
3) Disseminated intravascular coagulopathy: eg. onset within a few hours of starting treatment for acute myeloid leukaemia
Why does chemotherapy cause vomiting?
Give the 3 patterns of emesis seen
Due to direct action of chemotherapy drugs on the central chemoreceptor trigger zone (+ multifactorial)
Patterns of emesis
- acute phase 4 - 12 hours
- delayed onset, 2 - 5 days later
- chronic phase, may persist up to 14 days
When does Alopecia tend to occur during chemo and how may this vary during treatment course?
Hair thins at 2 - 3 weeks
May be total but may re-grow during therapy (difficult to predict)
….Help sometimes with scalp cooling
Give 3 chemo drugs associated with alopecia and one drug that is less so
Marked with doxorubicin, vinca alkaloids and cyclophosphamide
Minimal with platinums
Give 2 local skin toxicity effects of chemo
1) Irritation and thrombophlebitis of veins
2) Extravasation
What are the general skin toxicity effects associated with Bleomycin
Hyperkeratosis, hyperpigmentation, ulcerated pressure sores
Give 2 drugs associated with hyperpigmentation
(general skin toxicity effects)
- Busulphan
- Doxorubicin
- Cyclophosphamide
- Actinomycin D
Why may mucositis occur with chemo and in which part of the GIT is it usually worst?
Give 3 presenting symptoms of this
Due to GIT epithelial damage. It may be profound and involve whole tract and is most commonly worst in the oropharynx
Presents as
- Sore mouth/throat
- Diarrhoea
- G.I. bleed
Give 2 chemo drugs associated with cardio-myopathies
1) Doxorubicin ++ (> 550 mg/m2)
2) High dose cyclophosphamide
Give 2 chemo drugs associated with Arrhythmias
1) Cyclophosphamide
2) Etoposide
Give 2 chemo drugs associated with pulmonary fibrosis (lung toxicity)
- Bleomycin
- Mitomycin C
- Cyclophosphamide
- Melphalan
- Chlorambucil
What is the most common dose limiting toxicity and most frequent cause of death from toxicity
Haematological Toxicity - different agents cause variable effects on degree and lineages ie. neutrophils and platelets
It is these effects of leukopenia etc that make it ‘dose limiting’
State the following for chemotherapy drugs:
- theraputic window
- side effects
- inter-subject variability
- treatment regimes
narrow theraputic window
significant side effects
high inter-subject variability ➞ dose needs to be altered for the individual patient
balanced treatment regimes required
Give 3 individual patient factors that influence dose of chemotherapy
1) their surface area and/or body mass index
2) drug handling ability (eg. liver function, renal function…dependent on metabolism and excretion routes)
3) general wellbeing (performance status and comorbidity)
Treatment phasing needs to take into account balance between what 4 things?
1) growth fraction
2) the ‘cell kill’ of each cycle of the chemotherapy regimen
3) marrow and GI tract recovery before next cycle
4) how tolerable is the regimen (short term organ toxicity, physical side effects and long term damage causing late effects)
Give 4 PK factors that cause variability for chemo treatment + examples
Abnormalities in:
1) absorption: N+V, compliance, gut problems
2) distribution: Weight loss, reduced body fat, ascites
3) elimination: liver/renal dysfunction, other meds
4) protein binding: low albumin, other drugs
Give 4 drugs which may increase plasma levels of the chemotherapy drug (and therefore side effects)
Drug-drug interactions
1) Vincristine + itraconazole (antifungal) leads to more neuropathy
2) Capecitabine (oral 5FU) + warfarin
3) Methotrexate + penicillin or NSAIDs
4) Capecitabine + St Johns Wort and grapefruit juice
Give 3 ways we can monitor the response of cancer to the treatment
1) Radiological imaging
2) Tumour marker blood tests
3) Bone marrow/cytogenetics
How can we monitor drug levels of Methotrexate during treatment?
Methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue
Give 2 ways we can monitor organ damage during chemo treatment
1) Creatinine clearance
2) Echocardiogram
Clinical Trials: how do the drugs get from bench to bedside?
What is ‘targeted drug therapy’ + examples
Using molecular biology to identify targets in:
- monoclonal antibodies
- cytokines
- inhibiting angiogenesis
- targeting gene expression
- signal transduction inhibitors
- interfering with the apoptotic pathways
- interfering with cell cycle control
Define a neoadjuvant vs an adjuvant
Neoadjuvant - given before surgery or radiotherapy for the primary cancer
Adjuvant - given after surgery to excise the primary cancer, aiming to reduce relapse risk eg breast cancer
Define the following:
- Palliative
- Primary
- Salvage
Palliative - to treat current or anticipated symptoms without curative intent
Primary – 1st line treatment of cancer.. In many haematological cancers this will be with curative intent, initially aiming for remissiom
Salvage – chemotherapy for relapsed disease
