Lecture 26 - Chemotherapy Flashcards
What type of drugs do we use to treat cancer?
CDK4/6 inhibitors
Tyrosine Kinase Inhibitors
Monoclonal antibodies
PARP inhibitors
Cytotoxic chemotherapy
What is the structure of DNA?
Double helix of nucleotides that are anti-parallel
What are nucleotides?
Sugar-phosphate-base
What are the purines?
Adenine
Guanine
What are the pyridimines?
Cytosine
Thymine (Uracil in RNA)
What is transcription?
DNA conversion to RNA
What is translation?
RNA conversion to amino acids which code for protiens
What are the stages in the cell cycle?
G1
S
G2
M
G0 not in the cell cycle
What is G0?
Stage not in the cell cycle where the cell is not growing to replicate
What is G1?
When the cell is carrying out its normal functions and producing protiens to prepare for DNA synthesis
What is S phase in the cell cycle?
DNA replicates
What is G2?
DNA moves to opposite poles of the cell and the cell prepares to divide
What is M?
Mitosis (cell division)
What type of cells do chemotherapy agents target?
Cells that are rapidly growing/dividing
What is the definition of growth fraction?
The proportion of cells dividing at any given time
What is growth fraction used to measure?
Tumour sensitivity to chemotherapeutic agents
What does a large growth fraction indicate in terms of sensitivity to chemotherapeutic agents?
Tumours with large growth factors = more responsive to chemo
So higher sensitivities
Why do multiple cycles of chemotherapy agents normally have to be used?
Tumours are Heterogeneous
So some cells are proliferating (killed by chemo), others dying or lying dormant (not killed) so multiple cycles are required to eradicate remaining and re-growing cells
What is the fraction cell kill hypothesis?
Where a given dose of chemotherapy is given which kills a constant PROPORTION of a tumour cell population rather than a constant number of cells
What is a neoadjuvant?
When chemotherapy is given before surgery or radiotherapy for the primary cancer
What is an adjuvant?
When a chemotherapy agent is given AFTER surgery to excise the primary ailing to reduce relapse risk (e.g breast cancer)
What is the palliative use of chemotherapy?
Treat current or anticipated symptoms without curative intent
What is the primary use of chemotherapy?
1st line treatment of cancer
Often in haematological cancers aims for curative intent and remission
What is the salvage use of chemotherapy?
For released disease
How does Growth fraction usually relate to the size of a tumour?
When tumour volume low, Growth fraction = High (so adjuvant chemotherapy given)
Tumour volume high = Low Growth Fraction (less actively dividing)
What are some highly sensitive tumours to chemotherapy?
Lymphomas
Germ cell tumours
Small cell lung cancer
Neuroblastoma
Wilms tumour
What are some cancers with low chemo sensitivity?
Prostate
Renal cell
Brain tumours
Endometrial
What is the very basic basis for how chemotherapy drugs work?
They interfere with the processes in cell growth and repair helping reduce cancer cells ability to grow and proliferate
What happens once the cancer cells get damaged by a chemotherapeutic agent?
Cant repair damage so apoptosis occurs
What is the general function if anitmetabolites?
Affect DNA synthesis
What is the general function if alkylating agents?
Affect/modify DNA
What point of the cell cycle do spindle poisons work at?
Mitosis (division)
What is an example of an alkylating agent?
Carmustine
What is the mechanism of action of Alkylating agents like carmustine?
Add alkyl groups leading to the DNA cross linking leading to defects in DNA replication
What are some examples of platinum compounds as chemotherapy agents?
Cisplatin
Oxaliplatin
What is the mechanism of action of platinum compounds like cisplatin and oxaliplatin as chemotherapy agents?
Forms palatinates inter and Intra strand adducts leading to inhibiton of DNA synthesis
What are 2 examples of Antimetabolites as chemotherapy agents?
5-fluorouracil
Methotrexate
What is the mechanism of action of 5-flurouracil as an antimetaboblite/chemotherapy agent?
Inhibits enzyme Thymidylate synthase
So less Thymidine is made
This leads to less dTMP (Thymidine base)
So inhibits/impairs DNA synthesis
What is the mechanism of action of Methotrexate as an anti metabolite/chemotherapy agent?
Inhibits Dihydrofolate REDUCTASE stopping dihydrofolate being converted to Tetrahydrofolate
So disrupts folate cycle impairing DNA synthesis leading to apoptosis
What are 2 types of spindle poisons?
Taxoids
Vinca alkaloids.
What stage of the cell cycle do spindle poisons work in?
Mitosis (premetaphase)
What is an example of a taxoid (spindle poison)?
Paclitaxel
What is the mechanism of action of taxoids like paclitaxel as a spindle poison?
Promotes assembly and prevents disassembly of spindle fibres
What is an example of a vinca alkaloid?
Vincrisitine
What is the mechanism of action of vinca alkaloids like Vincristine as spindle poisons?
Prevent spindle formation
What are the side effects of chemotherapy?
Affects rapidly dividing cells
Alopecia
Nausea + Vomiting
Myelosuppression
Renal failure
Cardio toxicity
Pulmonary fibrosis
Mucositis
Many side effects
What causes vomiting in chemotherapy?
Direct action of chemotherapy drugs on central Chemoreceptors trigger zone (CTZ)
What are the chemotherapy agents which cause the worst Alopecia?
Doxorubicin
Vinca alkaloids (vincristine)
Cyclophosphamide
What technique can be used to help reduce Alopecia with chemotherapy?
Scalp cooling caps
How do scalp cooling caps work to reduce Alopecia?
Reduce blood flow to the scalp
Less chemo agents reach the hair
What are some local skin toxicity problems seen with some chemotherapy agents?
Irritation
Thrombophlebitis of veins
Extravasation
What is extravasation?
When the chemo agent leaks out of the blood vessels leading to burns in the subcutaneous tissues
What are some toxic effects to the skin with bleomycin?
Hyperkeratosis
Hyperpigmentation
Ulcerated pressure sores
What are some chemotherapeutic drugs that can cause hyperpigmentation?
So what should patients avoid?
Bisulphan
Doxorubicin
Cyclophosphamide
Actinomycin D
Sunlight
What is damaged in mucositis and why is it often a side effect of chemotherapy?
How does it present:
GI tract epithelia damaged since they are rapidly proliferating
Worst in oropharynx
Sore mouth/throat
Diarrhoea
GI bleed
What are some chemo drugs that cause cardio-myopathy?
Doxorubicin
High dose cyclophosphamide
What should be done before giving a patient doxorubicin?
Echocardiogram
To see if heart function is good enough
What are some chemo drugs that can cause arrythmias (syncope, palpitations, dizziness)?
Cyclophosphamide
Etoposide
What are some chemotherapy drugs that can cause pulmonary fibrosis?
Bleomycin
Cyclophosphamide
Melphalan
Chlorambucil
Mitomycin C
What it’s the most common cause of death from chemotherapy toxicity?
Myelosuppression
What cells are commonly affected as a result of Myelosuppression by chemo agents?
Neutrophils
Platelets
Erythrocytes
What are some haematological risks of chemotherapy toxicity?
Neutropenic sepsis
Anaemia
Thrombocytopenia (Bleeding and bruising)
What are the chemotherapy agents causing ototoxicty and nephrotoxicity?
Cisplatin
Carboplatin
What are the chemotherapy agents causing peripheral neuropathy?
Vincristine
What are the main chemotherapy causing pulmonary fibrosis?
Bleomycin
Busulfan
What is the main side effect of methotrexate, 5-Flurouracil and other anti-metabolites azathioprine?
Myelosuppression
What chemotherapy drug is causes Haemorrhagic cystitis as a major side effect?
Cyclophosphamide
What are the 2 main drugs causing cardio toxicity?
Doxorubicin
Trastuzumab
What is the aim of combination therapy?
Balancing activity of the drug with its safety to Maximise treatment
What are some routes of adminstration of chemo drugs?
IV most common
PO (most convenient but depends on oral bioavailability)
SC
Intrathecal (into the CSF by lumbar puncture for a haematological malignancy)
What are some IV pumps for chemo drugs?
PICC line
Hickman line
What causes variability in pharmacokinetics in chemotherapy?
Abnormalities in absorption
Abnormalities in distribution
Abnormalities in elimination
Abnormalities in protein binding
What can cause abnormalities in chemotherapy drug absorption?
Nausea and vomiting
Compliance
Gut problems
What can cause abnormalities in chemotherapy drug distribution?
Weight loss
Reduced body fat
Ascites
What can cause abnormalities in chemotherapy drug elimination?
Liver and renal dysfunction
Other medications
What can cause abnormalities in chemotherapy drug protein binding?
Low albumin (malnourished patients)
Other drugs
What side effect does the interaction of vincristine and itraconazole have?
Neuropathy
If both capecitabine (oral 5-FU) and warfarin are being taken, what should warfarin be changed to?
DOAC like apixaban
What do you have to be careful prescribing with methotrexate?
Penicillin
NSAIDs
What should you be careful taking with capecitabine (oral 5-FU)?
St John’s Wort
Grapefruit juice
How can acute renal failure be caused by chemotherapy?
Rapid breakdown of tumour causes Hyperuricaemia
Urate crystals form in renal tubules causing AKI
What side effect can chemohave on the GI system in lymphoma?
GI perforation at site of tumour
Treatment of what cancer can lead to DIC?
Acute myeloid leukaemia
How can you monitor response of cancer in chemo?
Radiological imaging
Tumour markers in blood tests
Bone marrow/cytogenetics
How can you check chemo drug levels in blood and check for organ damage?
Drug assays
Organ damage:
-creatinine clearance
-echocardiogram
What determines the dose of chemotherapy drugs for a patient?
Surface area
BMI
How their organs can handle it
General well-being (comorbities)
