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What are the aims of chemotherapy?
To prolong survival and maintain good QOL
What is chemotherapy?
The use of cytotoxic drugs to kill tumour cells
True or false: there are chemotherapy drugs licences for use in animals?
False - only human chemotherapy drugs are used, none are licensed for animals
What are chemosensitive tumours?
Multicentric/disseminated tumours (lymphoma/leukaemia, high grade MCT)
What makes these tumours chemosensitive?
They are rapidly dividing and therefore sensitive to the drugs
What are chemoresistant tumours?
Solid, large, bulky tumours - poorly vasuclarised, necrotic centres, low cell division, low drug availability
When might we use chemotherapy on chemoresistant tumours?
Use surgery to remove the tissue bulk and stimulate division of any residual tumour cells. Then use chemotherapy to kill off residual primary tumour cells as they are stimulated to divide post surgery. Or use chemotherapy to delay the growth of subclinical metastases which are dividing rapidly at this phase of growth
List the different steps of the cell cycle.
G1, S phase, G2, M phase. Also G0.
In what stage of the cell cycle will cells not be affected by chemotherapy drugs?
G0 - cells are not dividing
List the different categories of chemotherapy drugs
- Vinca alkaloids
- Alkylating agents
- Anti-tumour antibiotics
- Miscellaneous (cisplatin, l-asparginase)
What point of the cell cycle do vinca alkaloids affect?
What is the mechanism of action of vinca alkaloids?
Inhibit the mitotic spindle and prevent chromosomes being pulled apart in cell division
What is a rare side effect of vinca alkaloids?
Give an example of a vinca aklaloid
How are vinca alkaloids administered?
What are vinca alkaloids used to treat?
Lymphoma protocols, MCT protocols
What stage of the cell cycle do antimetabolites work at?
What is the mechanism of action of antimetabolites?
Analogues of the DNA nucleotides which target the synthesis of purines and pyrimidines and interfere with DNA synthesis
What are cytosine arbinoside, mtheotrexate and hydroxyurea used to treat?
Why can 5-Fluorouracil not be used in cats? What is it used to treat?
- As it causes neurological side effects
What stage of the cell cycle do alkylating agents affect?
What is the mechanism of action of the alkylating agents?
Incorporate an alkyl group into DNA, forming covalent bonds that cause inter/intrastrand cross linking which inhibits RNA/protein synthesis, replication and transcription
What is cyclophosphamide widely used for?
Leukaemia/lymphoma due to its pronounced effect on lymphocytes
What organs must be functional to administer cyclophosphamide to a patient?
- Liver - metabolism is essential for cytotoxicity
- Kidney - renal excretion
What is a side effect of cyclophosphamide?
What stage of the cycle do anti-tumour antibiotics affect?
What is the mechanism of action of anti-tumour antibiotics?
- Intercalate in DNA to prevent RNA/protein synthesis.
- Inhibit topomerase II
- Produce free radicals
Doxorubicin, epirubicin and mitoxantrone are collectively known as?
What is a side effect of doxorubicin?
Cardiotoxicity - must monitor heart function to ensure it is not impaired by cumulative dose
What is cisplatin?
A platinum compound with two chlorine atoms and two ammonia groups
What is the mechanism of action of cisplatin?
Similar to alkylating agents i.e. intrastrand crosslinking
What are the side effects of cisplatin?
- Nephrotoxicity - hydration and diuresis are essential
- Vomiting and nausea - may require anti-emetics
What compound is now used widely instead of cisplatin and why?
Carboplatin - it is a derivative with less nephrotoxicity
What is the mechanism of action of L-asparginase?
It breaks down aspargine into aspartic acid and ammonia. Tumour cells cannot make their own aspargine but normal cells cannot therefore it is selectively toxic to tumour cells.
What are side effects of L-asparginase?
- Anaphylatic reactions
Give an example of a commonly used glucocorticoid for chemotherapy
Dexamethasone or prednisolone
What does an a) high b) low dose of glucocorticoid do?
- a) inhibits lymphocyte proliferation
- b) reduced inflammation/stimulates appetite
When might single drug protocols be used in chemotherapy?
If the cell type is particularly sensitive or in combination with surgery and/or radiotherapy to prevent metastases in solid tumours
What are the three types of combined drug protocols for chemotherapy?
COP, CHOP and ALP
What are advantages of using combined drug protocols?
- Different drugs have different modes of action and act at different stages of the cell cycle
- They have different modes of resistance
What should be avoided in combined drug protocols?
- Drug toxicities should not overlap
- Drugs should not interfere with each other
What is the fraction kill hypothesis?
A given dose of chemotherapy drug kills a fixed percentage of the mass of cells in a tumour rather than a fixed number. Therefore cancer drugs should be used at the highest possible dose to effect the highest possible fractional kill in conventional chemotherapy.
List some side effects of chemotherapy drugs
- Perivascular reaction ie pain, erythema, moist desquamation, necrosis
- Vomiting, diarrhoea, anorexia, mucositis, colitis
- Myelosuppresion - anaemia, thrombocytopenia, neutropenia
- Haemorrhagic cystitis
How do cells acquire drug resistance?
- Decreased uptake
- Increased target enzyme levels
- Decreased drug activation
- DNA repair
- Drug cleavage
- Increased efflux
How does multi drug resistance occur?
This is due to ATP binding cassette transporters that efflux drugs
What is the most common ATP binding cassette transporter responsible for multi drug resistance?