Overview of Cancer Chemotherapy Flashcards
What are the general causes of cancer?
mutations in DNA resulting in production of altered cells which have changes in proliferating mechanisms
changes in the DNA caused by covalent modification, spontaneous or genetic predisposition, ionising/UV radiation, chemical carcinogens
Describe the immune response against cancer
Immune response against cancer is poor, so are body defences, and high percentage kill needed, biochemistry is same as that of regular cells
Traditional Agents
Alkylating agents, antimetabolites, cytotoxic antibiotics, plant derivatives
How do alkylating agents work against cancer?
Alkylating agents form covalent bonds with nucleophilic substances in the cell and bind to DNA (intrastrand linking) to cause changes.
It tends to alkylate the 7-Nitrogen guanine residues, which exist in the keto-tautomer, to open the imidazole ring (depurination) ; when this becomes more alkylated it turns into an enol-tautomer, which can mispair with thymine during DNA synthesis to create a mutation which can trigger cell death by apoptosis
Cyclophosphamide (Nitrogen Mustards)
Alkylating agent which is activated in liver by P450 enzymes and aldophosphamide is transported to other tissues where it forms phosphoramide (cytotoxic)
What is an example of an Ethylenemine alkylating agent?
Thiotepa
What is an example of an Alkyl Sulfonate alkylating agent?
Busulfan
What is the function of alkyl sulfonates?
Selective effect on bone marrow, depresses the formation of granulocytes and platelets, little to no effect on lymphoid tissue or the GI tract
Used in chronic granulocytic leukaemia
What class of alkylating agent does temozolomide belong to?
Hydrazines/Triazines
What are two examples of Nitrosoureas alkylating agents?
lomustine, carmustine
In what pathology are Nitrosoureas alkylating agents used, and why?
Lipid soluble and can cross the blood brain barrier, may be used against brain tumours
What is an example of a platinum-based alkylating agent?
Cisplatin
What is the function of cisplatin in combating tumors?
Water soluble, activated by aqueous environment, causes local denaturation of DNA chain
What are the main categories of antimetbolite chemotherapy agents?
Antifolates, Antipyrimidines, Antipurines
Name an Antifolate Chemotherapy Agent
Methotrexate
Name two anti-pyrimidine chemotherapy agents
5FU, gemcitabine
What are three examples of antipurine antimetabolite chemotherapy agents?
Mercaptopurine
Thioguanine
Fludarabine
What are some properties of antifolate antimetabolites?
Folate analogue, usually given orally, low lipid solubility, polyglutamated which means it can be retained within cells for weeks
How does the antipyrimidine 5FU work to fight cancer?
5FU interferes with thymidylate synthesis to prevent formation of DTMP to prevent DNA synthesis - “fraudulent nucleotide”
How does cytarabine antipyrimidine work?
Analogue of cytosine when phosphorylated it inhibits DNA polymerase
How does the gemcitabine antipyrimidine work to fight cancer?
Gemcitabine is an analogue of cytarabine: when phosphorylated it inhibits DNA polymerase
How does Mercaptopurine work to fight cancer?
Mercaptopurine is converted to 6-mercaptopurine-ribose phosphate called “Lethal Synthesis” which inhibits synthesis of purines
How does the antipurine fludarabin work to fight cancer?
Fludarabin in its triphosphate form inhibits DNA polymerase
What are the main classes of antibiotic chemotherapy agent?
Anthracyclines
Dactinomycin
Bleomycin
Mitomycin
How do anthracycline agents work to fight cancer?
Binds to DNA and inhibits both DNA and RNA synthesis and its main cytotoxic action appears to be mediated through an effect on topoisomerase II, the activity of which is markedly increased in proliferating cells.
During replication of the DNA helix, doxorubicin intercalates in the DNA and stabilises the DNA topoisomerase II complex after the strands have been nicked, causing the process to seize up and stop
How does dactinomycin work to fight cancer?
Dactinomycin intercalates in the minor groove of DNA between adjacent guanine-cytosine pairs, interfering with the movement of RNA polymerase and so preventing transcription.
How does bleomycin work to fight cancer?
Bleomycin degrades preformed DNA, causing chain fragmentation and release of free bases - it works in the oxidation of iron and generation of superoxide radicals and so is most effective in the G2 phase of cell cycle
How does mitomycin work to fight cancer?
After its enzymatic activation in cells, mitomycin functions as a bifunctional alkylating agent at O6 of guanine, which crosslinks DNA and may also degrade DNA through the generation of free radicals
How do plant-derived spindle poisons work to fight cancer?
They affect microtubule function and prevent mitotic spindle formation
How do vinca alkaloids work to fight cancer cells? Name two vinca alkaloids.
(vincristine, vinblastine) - bind tubulin and prevent polymerisation into microtubules
How do plant-derived taxanes work to fight cancer? Name two taxanes.
Paclitaxel (taxol), docetaxel
stabilises/freezes microtubules
How do camptothecins work to fight cancer? Name one example.
binds to and inhibits topoisomerases
irinotecan
How does etoposide work to fight cancer?
inhibits mitochondrial function, nucleoside transport and topoisomerase II
Tumour Lysis Syndrome
A metabolic emergency that occurs due to rapid cell lysis & large amounts of cell metabolites in blood during chemotherapy.
Characterised by hyperuricemia, hyperphosphatemia, hyperkalaemia, and hypocalcaemia
Can lead to acute renal failure, cardiac arrest, death
Risk assessment prior to therapy and closely monitored
Dialysis may be required
Which chemotherapy agents tend not to cause myelosuppression?
vincristine and bleomycin
define myelosuppression
reduced production of cells which provide immunity, oxygen transport and clotting
