[13] Chemotherapy Flashcards
What does chemotherapy involve?
The use of pharmacological agents to kill tumour cells
What can chemotherapy be effective in treating?
Both primary tumours and metastatic spread
How does chemotherapy work?
It acts at different stages of the cell cycle, and exerts its effects primary by 3 different mechanisms;
- Altering the chemistry of nucleic acids
- Interfering with DNA or RNA synthesis
- Disrupting mechanisms of cell devision
Are chemotherapy agents selective?
Most of the common agents act in a non-selective manner
What is meant by most chemotherapy agents acting in a non-selective manner?
They not only damage cancer cells, but affect normal dividing cells
What normal dividing cells are particularly affected by chemotherapy?
- Hair follicles
- Bone marrow
- Gastrointestinal mucosa
What is the result of chemotherapy agents acting in a non-selective manner?
It produces side effects that limit the dose that can be administered and the recovery time before the next dose can be given
How is most chemotherapy given?
As a combination of drugs administered IV on an intermittent basis
On average, how often is an individual cycle of chemotherapy repeated?
Every 21-28 days
How many cycles does a typical course of chemotherapy consist of?
6
What is the purpose of intermittent dosing in chemotherapy?
Malignant cells have less capacity for repair than normal cells, and intermittent dosing exploits the fact that tumour cells recover from cytotoxic damage more slowly than normal cell populations
What does each sequential treatment cycle of chemotherapy allow?
Normal stems cells time to recover
What is the chemotherapy drug dose usually calculated from?
Surface area of patient, based on height and weight
What is pharmacodynamics?
The study of the effect that drugs have in the body
Why is pharmacodynamics significant in chemotherapy?
In terms of dose-limiting toxicity, which can be used to determine the maximum possible dose in an individual patient
What is pharmacokinetics?
The study of the effects that the body has on the drug
What can pharmacokinetics be modified by?
- Renal and hepatic function
- Drugs clearance from the circulation
What is the result of the potential for modification of pharmacokinetics with chemotherapy?
Careful monitoring of the patient’s biochemistry, renal, liver, and bone marrow function is essential during chemotherapy treatment
What is the downside of chemotherapy?
It is highly toxic with the potential for life-threatening side effects
How is the potential for life threatening side effects of chemotherapy reduced?
- Requires supervision from specialists
- Patients should have careful assessment prior to commencement of treatment, and prior to each cycle
What is a reliable predictor to tolerance of chemotherapy treatment?
Patient fitness
What is the result of poor fitness when having chemotherapy?
- Will not tolerate chemotherapy as well
- Increased risk of adverse effects
How is the effects of poor fitness in chemotherapy patients combatted?
It is important to assess the patient’s performance status to determine patient suitability for chemotherapy and appropriate dosing of treatments
What is growth fraction?
The percentage of cells in a tumour mass that are actively dividing
Give an example of a cancer with a high growth fraction
Burkett’s lymphoma
What is the growth fraction in Burkett’s lymphoma?
50% (doubling time of 24 hours)
Give an example of a cancer with a low growth fraction?
Some adenocarcinomas
What is the growth fraction in some adenocarcinomas?
Immeasurable (doubling time of up to 200 days)
What can chemotherapy agents be divided into?
- Cell cycle independent
- Cell cycle dependent
What can chemotherapy agents that are cell cycle dependent be further subdivided into?
- Phase non-specific
- Phase specific
What is meant by a chemotherapy agent being phase non-specific?
They are equally active against cells in all phases of the cell cycle except G0
What is meant by a chemotherapy agent being phase specific?
It is only active against cells in one phase of the cycle
How can if a chemotherapy is phase specific or phase non-specific be utilised clinically?
These features can be used to design drug regimen combinations and schedules that take advantage of individual drug characteristics
Where kind of cells does the normal process of tissue renewal involve?
Both actively proliferating and quiescent stem cells
What is true of the quiescent stem cells that are involved in normal tissue renewal?
They are in the G0 phase of the cell cycle
Why is it significant that quiescent stem cells involved in normal tissue renewal are in the G0 phase of the cell cycle?
Because most anti-cancer agents are not active against these cells
What is a single clonogenic malignant cell capable of?
Multiplying and ultimately killing the host
What does the fact that a single clonogenic malignant cell is capable of multiplying and ultimately killing the host imply?
That cure depends on total cell eradication of all malignant cells
Is it always the case that cure depends on total cell eradication in cancer?
No
Why is it not the always case that cure depends on total cell eradication of all malignant cells?
There is evidence that in some cancers, there is a host response that may augment chemotherapeutic cancer kill
What is the simplest model of tumour growth?
Exponential
When is the exponential model of tumour growth true?
Only for microscopic lesions with fewer than 10^9 tumour cells
What does the growth curve of a clinically palpable cancer follow?
A Gompertzian function
What is a Gompertzian function?
When the rate of growth slows as the tumour increases in size
Why does the rate of growth of a tumour slow as it increases in size?
Due to limits imposed by the tumour micro-environment
What is the result of larger volume cancers having smaller growth fractions?
They may be inherently less sensitive to phase-specific agents
What is the rationale for adjuvant chemotherapy?
Small or micrometases may be more sensitive to chemotherapy
What is the dose response for most chemotherapies?
Steep dose response
What is meant by a steep dose response to chemotherapy?
There is a greater cell kill demonstrated at higher drug doses
Other than dose, what other factors might influence cell kill?
- Dose intensity
- Density
Is resistance to chemotherapy innate or acquired during treatment?
Can be either
What features make it more likely that drug-resistance cells will be present?
- Larger tumour mass
- Moe doublings occurring before treatment
When can multi-drug resistance be observed in cancer cells?
After exposure to a single drug
What are cancer cells that are multi-drug resistant after being exposed to a single drug usually susceptible to?
- Alkylating agents
- Anti-metabolites
What is multi-drug resistance associated with?
Increased expression of the membrane protein p-glycoprotein
What is the function of p-glycoprotein?
Functions as an active pump transporting toxic alkaloids out of the cell
How is the risk of resistance to chemotherapy minimised?
Anti-cancer drugs are often combined
What are the different classes of chemotherapy?
- Alkylating agents
- Intercalating agents
- Topisomerase I/II inhibitors
- Antimetabolites
- Tubulin binders
What can alkylating agents be subdivided into?
- Bifunctional alkylating agents
- Monofunctional alkylating agents
Give an example of a bifunctional alkylating agent
Cyclophosphamide
Give an example of a monofunctional alkylating agent
Dacarbazine
How do bifunctional alkylating agents work?
By transferring an alkyl group to the purine bases of DNA, which forms covalent bonds between two different bases, resulting in interstrand or intrastrand cross links, therefore inhibiting DNA synthesis
What are the purine bases of DNA?
- Adenine
- Guanine
What is the result of bifunctional alkylating agents acting by inhibiting DNA synthesis?
They act during the S phase of the cell cycle
Can bifunctional alkylating agents act on more than one base?
Yes
Are bifunctional alkylating agents more or less cytotoxic than monofunctional alkylating agents?
More
How do monofunctional alkylating agents work?
They cannot form cross-links, but form adducts. This inhibits DNA synthesis
What is the result of monofunctional alkylating agents acting by inhibiting DNA synthesis?
They act during the S phase of the cell cycle
What is the disadvantage of monofunctional alkylating agents compared to bifunctional?
They are more mutagenic and carcinogenic than bifunctional
What can intercalating agents be subdivided into?
- Platinum compounds
- Anthracyclines
- Anthraquinones
Give 3 examples of platinum compounds?
- Cisplatin
- Carboplatin
- Oxaliplatin
How do platinum compounds act as chemotherapy agents?
They intercalate and disrupt the steric integrity of the DNA double helix, but also form intrastrand adducts like those formed by alkylating agents
Give 3 examples of anthracyclines
- Doxorubicin
- Danorubicin
- Epirubicin
How do anthracyclines work?
They intercalate into the DNA major groove between base pairs of the DNA double helix. This disrupts the steric integrity of the DNA helix, and blocks DNA replication
Is anthracyclines action base specific?
No
Why is anthracyclines action not base specific?
Because it’s action is non-covalent
What is the main target for anthracyclines?
The enzyme topoisomerase II
Give an example of a topoisomerase I inhibitor
Topetecan
Give an example of a topoisomerase II inhibitor?
Etoposide
What do topoisomerase enzymes do?
Prevent DNA strands from becoming tangled
How do topoisomerase enzymes prevent DNA strands from becoming tangled?
By cutting DNA and allowing it to wind or unwind
What does topoisomerase I do?
Breaks single-stranded DNA and relieves torsion
In what phase of the cell cycle to topoisomerase I inhibitors act?
S phase
What do topoisomerase I inhibitors do?
They precent the re-ligation step of the nicking-closing reaction, trapping topoisomerase I in a covalent complex with the DNA
What does topoisomerase II do?
It breaks both strands of DNA, and allows the other strange to pass through the re-ligate
What do topoisomerase II inhibitors cause?
Double-stranded DNA breaks
What can anti-metabolites be divided into?
- Anti-folates
- Pyrimidine analogues
- Purine analogues
What are antimetabolites structurally related to?
Natural compounds
What do antimetabolites do?
Inhibit the metabolism of compounds necessary for DNA, RNA, or protein synthesis
When in the cell cycle are most anti-metabolites active?
During the S phase
Give two examples of anti-folates
- Methotrexate
- Ralitrexed
Give 3 examples of pyramidine analogues
- 5-FU
- Gemcitabine
- Cytosine arabinoside
Give 2 examples of purine analogues
- 6-metacaptopurine
- 6-thioguanine
What can tubulin binders be subdivided into?
- Vinca alkaloids
- Taxanes
Give 2 examples of vinca alkaloids
- Vincristine
- Vinblastine
How do vinca alkaloids work?
By binding to the tubulin dimer and preventing the assembly of microtubule filaments, therefore interfering with the functinon of the mitotic spindles and preventing cell division during the M phase of the cell cycle
Give 2 examples of taxanes
- Paclitaxel
- Docetaxel
How do taxanes work?
Binding to tubulin as a polymerised molecule, and preventing the disassembly back into dimeric form
What stage of the cell cycle do taxanes act in?
M phase
Give 3 examples of antibodies used in the treatment of cancer
- Rituximab
- Bevaxizumab
- Trastuzumab
How do antibodies work in cancer?
By binding to cell surface proteins expressed in target tissue. High-affinity binding prevents the normal ligand from attaching, and therefore inhibits the normal activation of the receptor. This diminishes the intracellular signals that drive cellular processes, such as angiogenesis and cell growth
Give 3 examples of kinase inhibitors used in chemotherapy
- Imatinib
- Erlotinib
- Lapatinub
How do kinase inhibitors work in chemotherapy?
They are small molecules which bind to the intracellular domains of a cell surface receptor and prevent activation of the intracellular signals that drive cellular processes
What can the adverse effects of chemotherapy be classified based on?
The time of onset
When are early effects of chemotherapy seen?
During treatment, or within the first few weeks of its completion
When do intermediate effects of chemotherapy occur?
Several weeks to months after completion of treatment
What are the late effects of chemotherapy?
Months to years after treatment
Are late effects of chemotherapy common?
No, they are rare
What are the categories of side effects of chemotherapy?
- Cardiovascular
- Respiratory
- Gastrointestinal
- Neurological
- Urogenital
- MSK
- Skin
- Other
What are the cardiovascular side effects of chemotherapy?
- Cardiomyopathy
- Acute coronary syndrome
- Arrhythmias
- Heart failure
What are the respiratory side effects of chemotherapy?
- Pulmonary fibrosis
- Pleuritic pain
What are the gastrointestinal side effects of chemotherapy?
- Nausea and vomiting
- Gastritis and oesophagitis
- Constipation
- Diarrhoea
- Stomatitis
- Hepatic dysfunction
What are the neurological side effects of chemotherapy?
- Focal neurological signs
- Ototoxicity
- Sensory neuropathy
- Motor neuropathy
- Memory changes
- Personality changes
What are the urogenital side effects of chemotherapy?
- Cystitis
- Nephropathy
- Premature gonadal failure
- Amenorrhoea
What are the MSK side effects of chemotherapy?
- Arthralgia
What are the skin side effects of chemotherapy?
- Rashes
- Hair loss
- Hypersensitivity
- Hand-foot syndrome
- Photosensitivity
- Skin hyperpigmentation
What are the other side effects of chemotherapy?
- Anaemia
- Pancytopenia
- Thrombocytopenia
What is extravasation?
When during administration the drug leaks into into the surrounding SC tissue
What is the consequence of extravasation of chemotherapy?
Local inflammatory reaction at the infusion site
What are the clinical features of the inflammatory reaction caused by extravasation of chemotherapy?
- Pain
- Redness
