Cancer Chemotherapy Flashcards
(45 cards)
What is neoplasia?
A new growth- uncontrolled proliferation of abnormal forms of the body’s own cells
What are the 3 characteristics of cancer cells?
1) Uncontrolled proliferation
2) Invasiveness
3) Metastasis
What are the 2 causes of cancer?
1) Mutations in the DNA causing the cell’s proliferation mechanism to change
2) Changes to the DNA caused by covalent modification:
• Spontaneous or genetic predisposition
• Ionising radiation or UV radiation
• Chemical carcinogens
What are the 3 categories of treatments?
1) Surgical excision
2) Radiotherapy
3) Chemotherapy
Why is it hard to treat cancer?
- The body’s own immune response against the cancer cells is poor
- The body defences are poor
- The tumour cells are recognised as ‘self’
- The biochemistry of the tumour cells and the cancer cells are the same so it is hard to get drugs that act on just the cancer itself
What are the 4 traditional types of Chemotherapy agents ?
1) Alkylating agents
2) Antimetabolites
3) Cytotoxic antibodies
4) Plant derivatives
Which is the most common chemotherapy agent?
Alkylating agents
Broadly speaking, how do alkylating agents work?
- Forms covalent bonds with the DNA
- Causes the intrastrand cross linking of DNA which causes a conformational change in the DNA helix and the cell either has to fix this or it will die by apoptosis
- Guanine usually exists as a keto tautomer which can pair with cytosine
- Alkylation of N7 on the guanine becomes alkylated making it more acidic and it forms a enol tautomer which can pair with thymine
- This destabilises the imidazole ring which can be opened resulting in deprivation (excision of guanine)
- This resulting damage triggers cell death by apoptosis
What are the major groups of alkylating agents?
- Nitrogen mustards
- Alkyl sulphonates
- Nitrosoureas
- Platinum based compounds
Give an example of a nitrogen mustard alkylating agent and explain its mechanism of action and what category it is classed in
Cyclophosphamide
• Activated in the liver by p450 mixed function oxidases to become Aldophosphamide
• Aldophosphamide is transported to other tissues and then becomes phosphoramide which is cytotoxic and kills cancer cells
• It is a type of alkylating agent
Which drug is used to minimise negative side effects of Cyclophosphamide?
Mensa
• Counteracts the effects of acrolein a cytotoxic by product
Give an example of a alkylsulphonate and describe how it works and what it is used to treat and what category it is classed in
Busulphan
• Has a selective effect on the bone marrow
• Little to no effect on the GI tract or the lymphatics
• Used to treat chronic granulocytic leukaemia
• It is an alkylating agent
Give two examples of Nitrosoureas and describe how it works and what it is used to treat and What category is it classed in
Lomustine, Carmustine
• Lipid soluble so can cross the blood brain barrier
• Treatment of brain and meninges
• It is a type of alkylating agent
Give an example of a Platinum based compound and describe how it works and what category it is classed in
- Cisplatin
- Platinium atom core surrounded by two Chlorine and 2 ammonia
- One chlorine dissociates when it enters into the cell, leaving a reactive complex that reacts with water then it interacts with DNA
- Causes intrastrand cross linking of the DNA chain between N7 and O6 of the adjacent guanine molecules resulting in the local denaturation of the DNA chain
- It is a type of alkylating agent
What are the 3 major groups of Antimetabolites?
1) Antifolates
2) Antipyrimidines
3) Antipurines
Give and example of an antifolate and describe how it works and what cateogory it is classed in
Methotrexate
• Folate analogue
• Low lipid solubility- doesn’t cross the blood brain barrier
• Polyglutamated so it is retained within the cells for weeks
• The target is DHFR (which is involved with one carbon metabolism)
• it is an antimetabolite
Give two examples of antipyrimidines and describe how they work and what category they are classed in
Fluorouracil (5-Fu)
• Interferes with the enzyme Thymidylate synthesise which converts DUMP to DTMP
• Converted into a fraudulent nucleotide FDUMP which cannot be converted into DTMP
Cytarabine
• Analogue of cytosine which has an arabinose instead of a ribose
• Undergoes phosphorylation to become cytosine arabinose triphosphate
• Inhibits DNA polymerase
They are both a type of antimetabolite
Give three examples of antipurines and describe how two of them work and what category it is classed in
Mercaptopurine
• Converted to 6-mercaptopurine-ribose phosphate called lethal synthesis
• Inhibits enzymes involved in the de novo synthesis of purines - fraudulent nucleotide
Fludarabine
• Inhibits DNA polymerase in its triphosphate form
Thioguanine
They are all a type of antimetabolite
What are cytotoxic antibiotics and what are the 4 main categories?
Antitumour antibiotics which have a direct action on DNA
1) Anthracyclines
2) Dactomycin
3) Bleomycin
4) Mitomycin
What is an example of an Anthracyclines and how does it work? What category is it classed in?
Doxorubicin
• Binds to DNA and inhibits both DNA and RNA synthesis
• Has an effect on topoisomerase II which is increased in proliferating cells
• During replication, reversible swivelling needs to take place to prevent tangling
• The topoisomerase II nicks both of the DNA strands and then reseals the breaks
• Doxorubicin intercalates in the DNAand stabilises the DNA topoisomerase II complex, causing the process to seize up
It is a type of cytotoxic antibiotics
How does Dactomycin work and what category is it classed in?
• Intercalates in the minor groove of DNA between adjacent Guanosine- Cytosine pairs, interfering with the movement of RNA polymerase, preventing transcription
It is a type of cytotoxic antibiotics
How does Bleomycin work and what category is it in?
• Degrades preformed DNA
• Oxidises the iron and generates superoxide hydroxyl radicals
• Most effective in the g2 phase of the cell cycle but it is also active against non-dividing cells
It is a type of cytotoxic antibiotic
How does Mytomycin work and what category is it in?
• Acts as a bifunctional alkylating agent, alkylating at o^ of guanine
• Cross links DNA and may also degrade the DNA through the generation of free radicals
It is a type of cytotoxic antibiotic
What are the five plant derivatives that are used in Chemotherapy?
1) Spindle poisons
2) Vinca alkaloids
3) Taxanes
4) Camptothecins
5) Etoposide
