Cancer Chemotherapy Flashcards
How have new cancer drugs been discovered?
- Random chance
- Screening of compounds
- Chemical engineering
- Molecular targetting
Give an example of chemotherapy drug that was found by chance
Cisplatin
How was cisplatin discovered?
When conducted microbiological experiments in which electric currents were passed through E Coli, it was found that platinum electrodes stopped E Coli growth
Give an example of a chemotherapy drug that was found through screening of compounds
Trabectedin
How was trabectedin discovered?
The National Cancer Institute carried out screening of plant and marine organism material for anti-cancer activity, and found that the extract of a sea squirt had promising activity. It was then found that trabectedin was the active moiety
Give an example of a chemotherapy drug that was discovered using chemical engineering
Taxotere
How was taxotere developed?
It was found that paclitaxel could be used as a chemotherapy drug, however it could only be obtained from the Pacific Yew stem bark, meaning it was of limited consequences and very expensive, so taxotere was developed by copying the chemical structure
Give an example of a drug discovered using molecular targeting approaches
Imatinib
What is imatinib?
A Bcr-Abl tyrosine kinase inhibitor
What are the advantages of molecular targeted drugs?
They are tumour selective drugs, and so are more efficacious with fewer side effects
What change in the treatment and prognosis of cancer is being made from development of molecular targetted drugs such as imatinib
It is transforming cancer into a chronic disease that can be treated and maintained instead of a fatal disease
Describe the gross structure of DNA
It is a double helix of nucleotides
What does a nucleotide consist of?
- Sugar
- Phosphate
- Base
What are the categories of bases?
- Purines
- Pyridimines
What are the purines?
- Adenine
- Guanine
What are the pyramidines?
- Cytosine
- Thymine
What factors determine the rate of tumour growth?
- Growth fraction
- Duration of cell cycle
- Rate of cell loss
What is the range of number of cells at which cancer is detectable?
Between 10^9 and 10^12 (at which point the host dies)
How long does the cell cycle take in cancer cells?
Between 9 and 43 hours
How long does mitosis take?
<1hr
How long does DNA synthesis take?
6-8 hours
How long does G1 phase take?
0-30 hours
How long does G2 phase take?
2-4 hours
In what stage of the cell cycle can chemotherapy and radiotherapy not work?
G0 - the dormant phase
What can be given to combat the fact that chemotherapy and radiotherapy don’t work in G0?
Drugs to enhance the number of cells in the cell cycle
Why is chemotherapy given in pulses?
Chemotherapy kills both cells of the bone marrow, and tumour cells. Cells of the bone marrow are able to recover quicker and more effectively, and so if you give in pulses, the tumour cells are killed but the bone marrow survives.
Why is it important to get the timing of chemotherapy pulses right?
- Too much delay means tumour cells can regrow
- Too frequent and you get bone marrow depletion, potentially leading to neutropenic sepsis
Give 5 examples of cancers that are highly sensitive to chemotherapy
- Lymphomas
- Germ cell tumours
- Small cell lung cancers
- Neuroblastoma
- Wilm’s tumour
Give 5 examples of tumours that are moderately sensitive to chemotherapy
- Breast
- Colorectal
- Bladder
- Ovary
- Cervix
Give 4 examples of tumours that have low sensitivity to chemotherapy
- Prostate
- Renal cell tumours
- Brain tumours
- Endometrial tumours
What might tumours that have modest and low sensitivity to chemotherapy require?
Other treatments with chemotherapy used as an adjunct
What are the classes of cytotoxic agents
- Antimetabolites
- Alkylating agents
- Spindle poisons
- Intercalating agents
What is the mechanism of action of antimetabolites?
They inhibit DNA synthesis
What is the mechanism of action of alkylating agents?
Disrupt DNA directly
What is the mechanism of action of intercalating agents?
Disrupt DNA transcription and DNA duplication
What is the mechanism of action of spindle poisons?
They inhibit mitosis
How do alkylating agents disrupt DNA?
They bind DNA strands together, so they cannot be separated during DNA replication and so replication is impaired
How do platinum compounds act as cytotoxic drugs?
They cause formation of platinated inter- and intrastrand adducts, leading to inhibition synthesis
How do DACH platinum adducts compare to platinum adducts?
They are bulky, and thought to be more effective in inhibiting DNA synthesis than platinum adduct
What happens if DNA cannot replicate?
Causes a single strand break, then a double strand break, causing apoptotic death
What is the problem with the DNA disruption of tumour killing?
It doesn’t always work, because the cell has repair mechanisms that fix DNA
Give two examples of antimetabolite chemotherapy drugs
- 5-fluorouracil
- Methotrexate
How does 5-flurouracil work?
It interferes with thymidylate synthase, which is a crucial enzyme for incorporating pyramidine and therefore essential for DNA synthesis
How does methotrexate work?
It inhibits dehydrofolate reductase, stopping the synthesis of purines
How are spindles involved in mitosis?
Once chromosomes are aligned at metaphase plates, spindle microtubules depolymerise, moving sister chromatids towards opposite poles
How do microtubule-binding agents affect microtubule dynamics?
- Inhibit polymerisation
- Stimulate polymerisation and prevent depolymerisation
Give an example of a class of drugs that promote spindle assembly and prevent disassembly
Taxoids
Give a class of drugs that prevent spindle formation
Vinca alkaloids
Where do chemotherapy drugs have to get to in order to have an effect?
The nucleus
What are the mechanisms of chemotherapy resistance?
- Decreased entry, or increased exit of agent
- Inactivation of agent in cell
- Enhanced repair of DNA lesions produced by alkylations
How might there be increased exit of chemotherapy agents?
Cell might express pumps to remove the drug
How might there be inactivation of the chemotherapy agent in the cell?
Proteins might bind with the agent to nullify its action
What are the indications for chemotherapy?
- -Cancer
- Rheumatoid arthritis
- Other conditions
What is predicted response in the same cancer dependant on?
- Performance score
- Clinical stage
- Prognostic factors or score
- Molecular or cytogenetic markers
What is the range of performance scores?
1 - 5, with 1 being fine and 5 being dead
At what performance scores will chemotherapy be given?
1-2, maybe 3 if have very sensitive tumour
What needs to be considered when prescribing chemotherapy?
Side effects vs anticipated best outcome
When are less side effects acceptable?
In palliative care
When are more side effects acceptable?
In paediatric leukaemia, which has 95% cure rate
What will the chemotherapy regimen consist of for many types of cancer?
A number of different drugs
What are the different routes of administration for chemotherapy?
- IV
- PO (oral)
- SC (subcutaneous)
- Into a body cavity -
- ntralesional
- Intrathecal
- Topical
- IM
What is the most common route of administration for chemotherapy?
IV
How can chemotherapy be delivered IV?
- Bolus
- Infusional bag
- Continuous pump infusion
What is the advantage of PO administration of chemotherapy?
Convenient
What is PO administration of chemotherapy dependant on?
Oral bioavailability
What is the advantage of SC administration of chemotherapy?
Convenient in a community setting
Give two examples of body cavities that chemotherapy could be administered into?
- Bladder
- Pleural effusion
What is meant by intralesional administration of chemotherapy?
Directly into the cancerous area
What should be considered with intralesional administration of chemotherapy?
pH
What is meant by intrathecal administration of chemotherapy?
Into the CSF
How is intrathecal administration of chemotherapy conducted?
- Lumbar puncture
- Omaya reservoir (directly into the ventricles)
Give two types of IV pumps
- PICC line
- Hickman line
Where does the Hickman line go into?
The subclavian vein
Why is the Hickman line tunelled under the skin?
To reduce the risk of infection, as there is immune action here
What is the advantage of IV pumps?
May have IV drug administered over several hours, so allows person to be mobile during this time
What are the side effects of chemotherapy?
- Mucositis
- Alopecia
- Pulmonary fibrosis
- Cardiotoxicity
- Local reaction
- Renal failure
- Myelosuppression
- Phlebitis
- Neuropathy
- Myalgia
- Sterility
- Cystitis
- Diarrhoea
- Nausea/vomiting
What chemotherapy adverse effects can occur due to the effect of treatment on the tumour
- Acute renal failure
- GI perforation at site of tumour
- Disseminated intravascular coagulopathy
How does treatment of the tumour cause acute renal failure?
Hyperuricaemia caused by rapid tumour lysis, leading to precipitation of urate crystals in the renal tubules
What kind of tumours may cause acute renal failure on treatment?
Very sensitive tumours
Why shouldn’t acute renal failure due to tumour treatment happen in modern medicine?
Because preventative drugs are given first
In what cancer is GI perforation at the site of the tumour reported?
Lymphoma
What is done to reduce the risk of GI perforation due to treatment of tumours?
It is recognised as a potenital problem, and the patient is given nil by mouth, so if there is a perforation there is less of a risk of peritonitis
When might disseminated intravascular coagulopathy occur?
Within a few hours of starting treatment for acute myeloid leukaemia
What causes vomiting in chemotherapy?
Multifactorial, but includes direct action of chemotherapy drugs on the central chemoreceptor trigger zone
What are the different patterns of emesis in chemotherapy?
- Acute phase, 4-12 hours after administration
- Delayed onset, 2-5 days later
- Chronic phase, may persist up to 14 days
- Anticipatory nausea, due to association
When does alopecia due to chemotherapy occur?
After 2-3 weeks
What drugs cause marked alopecia?
- Doxorubicin
- Vinca alkaloids
- Cyclophosphamide
What drugs minimise alopecia?
Platinum
What can be done to reduce alopecia caused by chemotherapy?
Scalp cooling
What happens in scalp cooling?
The scalp is cooled to <4 degrees before, during, and after chemotherapy
What local skin toxicities might chemotherapy cause?
- Irritation and thrombophlebitis of veins
- Extravasation
How can local skin toxicities be avoided?
Administer chemotherapy drug directly into the vein
What chemotherapy drug might cause general skin toxicities?
Bleomycin
What skin toxicities might be caused by bleomycin?
- Hyperketatosis
- Hyperpigmentation
- Ulcerated pressure sores
What chemotherapy drugs might cause hyperpigmentation?
- Busulphan
- Doxorubicin
- Cyclophosphamide
- Actinomycin D
Why might giving chemotherapy as a tablet lead to skin toxicity?
May lead to overcompliance as so convenient and doesn’t have constant monitoring, so patient might ignore skin problems
What is mucositis?
Gastrointestinal tract epithelial damage, which may be profound and involve the whole tract
Where is mucositis caused by chemotherapy most commonly worse?
In the oropharynx
How does mucositis present?
- Sore mouth/throat
- Diarrhoea
- GI bleed
What can the diarrhoea in mucositis lead to?
Dehydration and renal failure, can be life threatening
What cardiac problems can result from chemotherapy use?
- Cardio-myopathy
- Arrythmias
What chemotherapy drugs can cause cardio-myopathy?
- Doxorubicin (>550mg/m2)
- High dose cyclophosphamide
What chemotherapy drugs can cause arrythmias?
- Cyclophosphamide
- Etoposide
What chemotherapy drug can cause pulmonary fibrosis?
Bleomycin
Why must patients who have been treated with bleomycin carry a warning card?
Because if they present to A&E with shortness of breath, without this information they will be given oxygen, which worsens fibrosis
What is the most frequent dose limiting toxicity in chemotherapy?
Haemotological toxicity
What does RBC depletion lead to?
Anaemia
What does white cell depletion lead to?
Sepsis
What does platelet depletion lead to?
Bruising and bleeding
Why do cytotoxic chemotherapy drugs need a specialist to prescribe?
- Narrow therapeutic window
- Significant side effect profile
- Need for dose alterations
- Treatment phasing needs to be determined
What does the chemotherapy dose need to be altered based on?
- Patients surface area and/or body mass index
- Drug handling ability
- General wellbeing
What is considered in the drug handling ability of a patient?
- Liver function
- Renal function
What is considered in the general wellbeing of the patient?
- Performance status
- Comorbidities
What does treatment phase need to take into account?
The balance between;
- Growth fraction
- The ‘cell kill’ of each cycle of the chemotherapy regimen
- Marrow and GI tract recovery before the next cycle
- How tolerable the regimen is
What is considered in how tolerable a chemotherapy regime is?
- Short term organ toxicity
- Physical side effects
- Long term damage causing late effects
What causes variability in the pharmacokinetics of chemotherapy?
- Abnormalities in absorption
- Abnormalities in distribution
- Abnormalities in elimination
- Abnormalities in protein binding
What can cause abnormalities in absorption?
- Nausea and vomiting
- Compliance
- Gut problems
What causes abnormalities in distribution?
- Weight loss
- Reduced body fat
- Ascites
What is the problem with abnormalities in distribution due to ascites?
Chemotherapy agents sit in the ascites and don’t get metabolised, which can lead to lots of side effects
How can problems with distribution due to ascites be combatted?
Draining ascites prior to treatment
What causes abnormalities in elimination?
- Liver and renal dysfunction
- Other medications
What can cause abnormalities in protein binding?
- Low albumin
- Other drugs
What drug interacts with vincristine?
Itraconazole (a commonly used antifungal)
What drug interacts with capecitabine?
Warfarin
What drugs interact with methotrexate?
- Penicillin
- NSAIDs
What drugs interact with capecitabine?
St Johns Wort
What monitoring needs to be done during chemotherapy treatment?
- Response of the cancer
- Drug levels
- Checks for organ damage
How is the response of the cancer to chemotherapy monitored?
- Radiological imaging
- Tumour marker blood tests
- Bone marrow/cytogenetics
Give an example of drug level monitoring in chemotherapy
Methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue
How is organ damaged checked for in chemotherapy?
- Creatinine clearance
- Echocardiogram
What classes of chemotherapy drugs are beginning to be introduced?
- Hormones
- Targeted drug therapy
Give 7 examples of targeted drug chemotherapies
- Monoclonal antibodies
- Drugs inhibiting angiogenesis
- Drugs targeting gene expression
- Signal transduction inhibitors
- Drugs interfering with apoptotic pathways
- Drugs interfering with cell cycle control
- Cytokines
