Overview of Cancer Chemotherapy Flashcards
What is cancer?
Neoplasia - “New growth”
Uncontrolled proliferation of abnormal forms of the body’s own cells
What characteristics are seen in cancer cells that are not seen in normal cells?
1) Uncontrolled proliferation
2) Invasiveness
3) Metastases
What are the causes of cancer?
1) Mutations in DNA resulting in production of altered cells which have changes in proliferating mechanisms
2) Changes in the DNA caused by covalent modification
• Spontaneous or genetic predisposition
• Ionising radiation or UV radiation
• Chemical carcinogens
What are the three main ways to dealing with established cancers?
- 1) Surgical excision
- 2) Radiotherapy
- 3) Chemotherapy
What are the four types of traditional agent to deal with cancer?
- Alkylating agents
- Antimetabolites
- Cytotoxic antibiotics
- Plant derivatives
What are alkylating agents?
• Most commonly employed anti cancer drugs
• These are compounds which have the property of forming covalent bonds
with suitable nucleophillic substances in the cell under physiological conditions.
• Intrastrand crosslinking of DNA
How do alkylating agents work?
- Normally guanine residues in DNA exist predominantly in the keto tautomer
- This allows them to readily make Watson-Crick base pairs by hydrogen bonding with cytosine
- When the 7 nitrogen of guanine is alkylated it becomes more acidic and the enol tautomer is formed. (i.e. keto to enol)
- This modified guanine can mispair with thymine residues during DNA synthesis. i.e. G-T not G-C, creating a mutation.
- Also, alkylation of the 7 nitrogen destabilises the imidazole ring
- Opening of the imidazole ring (ring-cleavage)
- Depurination-excision of guanine residues and repair of DNA – opportunity for mutation
- The resulting damage to DNA by alkylating agents triggers cell death by apoptosis.
What are the major groups of alkylating agents?
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
How does the nitrogen mustard cyclophosphamide work?
- Cyclophosphamide activated in liver by P450 mixed function oxidases
- Aldophosphamide transported to other tissues where it forms phosphoramide (cytotoxic)
- Mesna counteracts effects of acrolein (haemorrhagic cystitis)
How does the alkylsuphonate busulphan work?
• Busulphan has a selective effect on the bone marrow, depressing the formation of granulocytes and platelets in low dosage and red cells in higher dosage. It has little or no effect on lymphoid tissue or the gastrointestinal tract. It is used in chronic granulocytic leukaemia.
How do the notrosoureas lomustine and carmustine work?
• Nitrosoureas; Lomustine and Carmustine because they are lipid soluble and can, therefore, cross the blood-brain barrier, may be used against tumours of the brain and meninges
How do the platinum based components like cisplatin work?
- Cisplatin is a water-soluble planar coordination complex containing a central platinum atom surrounded by two chlorine atoms and two ammonia groups.
- Its 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.
- It causes intrastrand cross-linking- probably between N7 and O6 of adjacent guanine molecules-which results in local denaturation of the DNA chain.
What are the major groups of antimetabolites?
1) Antifolates – e.g. methotrexate
2) Antipyrimidines – e.g. 5-FU, gemcitabine
3) Antipurines – e.g. mercaptopurine, thioguanine
Discuss methotrexate
Antifolate
• Folate analogue
• 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.
Discuss antipyrimidines
- Fluorouracil (5-FU) interferes with thymidylate synthesis (DTMP).
- It is converted into a fraudulent nucleotide FDUMP. Cannot be converted into DTMP.
- Cytarabine is an analogue of cytosine but has arabinose and not ribose attached.
- Undergoes phosphorylation to give cytosine arabinoside triphosphate.
- This inhibits DNA polymerase.
- Gemcitabine is an analogue of cytarabine.
Discuss antipurines
- Mercaptopurine, thioguanine, fludarabine
- Mercaptopurine is 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. Fraudulant nucleotide
- Fludarabine in its triphosphate form inhibits DNA polymerase.
What metabolite is fludarabine related to?
Adenosine
What metabolite is 5-FU related to?
Uracil
