Cancer Chemotherapy Flashcards
What is the percentage of cancerous cells which should ideally be killed by treatment ?
Enough for a clinical response
Describe the main treatment options for cancer.
1) Surgical excision
2) Radiotherapy
3) Chemotherapy
Identify the main groups of drugs used in chemotherapy.
- Alkylating agents
- Antimetabolites
- Cytotoxic antibiotics
- Plant derivatives
Identify the most commonly used group of drug in chemo.
Alkylating agents
Describe the mechanism of action of Alkylating agents.
• Have properties of forming covalent bonds with suitable nucleophillic substances in the cell under physiological conditions.
• Intrastrand crosslinking of DNA:
- Normally guanine residues in DNA exist predominantly in the keto tautomer.
- This allows them to hydrogen bond with cytosine.
- When the 7 nitrogen of guanine is alkylated it becomes more acidic and the enol tautomer is formed.
- This modified guanine can mispair with thymine residues during DNA synthesis. i.e. G-T not G-C
- Alkylation of the 7 nitrogen destabilises the imidazole ring causes ring cleavage
- This leads to depurination (excision of guanine residues)
- The resulting damage triggers cell death by apoptosis.
Identify the major groups of alkylating agents. Give one or two examples for each group.
1) Nitrogen mustards – e.g. cyclophosphamide
2) Ethylenimines - e.g. Thiotepa
3) Alkylsulphonates - e.g. Busulphan
4) Hydrazines and Triazines – e.g. Temozolomide
5) Nitrosoureas – e.g. lomustine, carmustine
6) Platinum based compounds – e.g. cisplatin
Describe the mechanism of action of cyclophosphamide.
- Cyclophosphamide (inactive) activated by P450 mixed function oxidases.
- Converted into hydroxycyclophosphamide, which forms aldophosphamide reversibly
- Aldophosphamide transported to other tissues where it forms phosphoramide (cytotoxic) + Acrolein (cytotoxic, responsible for unwanted effect)
Identify mesna and describe its importance in chemotherapy treatment.
Medication used in those taking cyclophosphamide to counteract effects of acrolein (to avoid haemorrhagic cystitis).
Describe the specific features of Busulphan.
- Selective effect on the bone marrow
- Depresses the formation of granulocytes and platelets in low dosage and red cells in higher dosage.
- Used in chronic granulocytic leukaemia
Describe the specific features of Nitrosoureas.
e. g. lomustine, carmustine
- Lipid soluble and
- Can cross the blood-brain barrier, may be used against tumours of the brain and meninges
Describe the specific features of Cisplatin.
- water-soluble planar coordination complex containing a central platinum atom surrounded by two chlorine atoms and two ammonia groups.
- action is analogous to that of the alkylating agents. When it enters the cell, Cl- dissociates leaving a reactive complex that reacts with water and then interacts with DNA
- causes intrastrand cross-linking- probably between N7 and O6 of adjacent guanine molecules-which results in local denaturation of the DNA chain.
Identify the main groups of antimetabolites. Give one or two examples for each group.
1) Antifolates – e.g. methotrexate
2) Antipyrimidines – e.g. 5-FU, gemcitabine, Cytarabine
3) Antipurines – e.g. mercaptopurine, thioguanine, fludarabine
Describe the specific features of Methotrexate.
• Folate analogue (structurally similar) so antifolate
• Usually given orally but can also be given
intramuscularly, IV or intrathecally.
• Low lipid solubility so does not cross the blood brain barrier easily.
• Polyglutamated which means it can be retained within cells for weeks.
Describe the specific features of Fluorouracil.
- Fluorouracil (5-FU) interferes with thymidylate synthesis (DTMP).
- It is converted into a fraudulent nucleotide FDUMP. Cannot be converted into DTMP
Describe the specific features of Cytarabin.
- Analogue of cytosine but has arabinose and not ribose attached.
- Undergoes phosphorylation to give cytosine arabinoside triphosphate.
- This inhibits DNA polymerase.
Describe the specific features of Gemcitabine.
• Analogue of cytarabine.
Describe the specific features of Mercaptopurine.
- Converted to 6- mercaptopurine-ribose phosphate, called “Lethal Synthesis”.
- 6 mercaptopurine-ribose-phosphate inhibits a number of enzymes in the de novo synthesis of purines.
- Results in fraudulant nucleotide
Describe the main features of Fludarabine.
In its triphosphate form, inhibits DNA polymerase.
Describe the structure of the following antimetabolites:
- 5-FU
- Gemcitabine
- Mercaptopurine
- Fludarabine
- 5-FU (F replaces H of uracil)
- Gemcitabine (2 Fs replaces H and OH on ribose ring)
- Mercaptopurine (S substitute in purine)
- Fludarabine (F replaces H of adenosine and arabinose replaces ribose)
Identify the main groups of Cytotoxic antibiotics.
- Anthracyclines
- Dactinomycin
- Bleomycin
- Mitomycin
Identify the main Anthracyclines.
Doxorubicin
Describe the mechanism of action of Doxorubicin.
• Generally, binds to DNA and inhibits both DNA and RNA synthesis.
- During replication of the DNA helix, reversible swivelling needs to take place around the replication fork in order to prevent the daughter DNA molecule becoming inextricably entangled during mitotic segregation.
- The swivel is produced by topoisomerase II, which nicks both DNA strands and subsequently reseals the breaks. Hence, the activity of topoisomerase II is markedly increased in proliferating cells.
- Doxorubicin intercalates in the DNA and its effect is to stabilise the DNA-topoisomerase II complex after the strands have been nicked, thus causing the process to seize up at this point.
Describe the mechanism of action of Dactinomycins.
- Intercalates in the minor groove of DNA between adjacent guanosine- cytosine pairs, interfering with the movement of RNA polymerase along the gene and thus preventing transcription
- Also evidence that it has a similar action to the anthracyclines on topoisomerase II
Describe the mechanism of action of Bleomycin.
- Group of metal-chelating glycopeptide antibiotics that degrade preformed DNA, causing chain fragmentation and release of free bases
- Action on DNA involves chelation of ferrous iron and interaction with oxygen, resulting in the oxidation of the iron and generation of superoxide and/or hydroxyl radicals
- Most effective in the G2 phase of the cell cycle and mitosis, but it is also active against non-dividing cells
