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Classical Chemotherapy - Coggle Diagram
Classical Chemotherapy
Anti tumour Antibiotics
Epirubicin now often favoured as it has fewer side effects – slight change to structure gives more rapid clearance and reduced formation of radicals
Doxorubicin also acts against a wide variety of solid tumours e.g. breast, bladder, ovary
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The anthracycline can also interact with molecular oxygen forming peroxide (O22-), superoxide(O2-) and hydroxyl radicals (.HO)
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The anthracyclines can be converted into unstable semiquinone radical by the action of NADPH cytochrome P450 reductase and other enzymes
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Anti Metabolites
Purine analogues
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6-Thiopurines – activated by hypoxanthineguanine phosphorylase transferase (HGPRT) which maintains the intracellular pool of purines
Nucleoside analogues
Also inhibits DNA and RNA polymerases and some nucleotide reductases (reduces bases available for incorporation)
Rapidly converted into cytosine arabinose triphosphate and incorporated into DNA but cannot then extend chain
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Methotrexate
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First discovered when it was observed that children with acute lymphoblastic leukaemia fared better when folate deficient.
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Methotrexate (and its analogues such as permetrexed) are DHFR antagonists causing inhibition of the enzyme and thus no THF
Dihydrofolate reductase (DHFR) is required to recycle DHF to THF to maintain the supply for thymidine synthesis
THF is then converted to N6, N10 methylene THF which donates a methyl group to uridine to produce thymidine
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Defined as substances that have similar structure to substrates for enzymes involved in DNA synthesis
Alkylating Agents
Cis-platin
DNA crosslinking which cannot be repaired: 1,2 intrastrand crosslinks most frequent, 1,3 intrastrand less common and more easily repaired
In solution one of the chlorides is slowly replaced by water
This is also easily displaced allowing the platinum to bind to an atom with a lone pair of electrons
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Busulfan: sed in chronic myeloid leukaemia (now slightly superseded) Also a pre bone marrow transplant ‘conditioning’ agent
Lung and severe hepato toxicity
Chlorambucil: Used mostly in chronic lymphocytic leukaemia.
Typical profile of chemotherapy side effects
Cyclophosphamide: Used in treatment of a range of cancers and some autoimmune diseases. Action of CYP450 enzymes produces active metabolite 4-hydroxycyclophosphamide
Extremely toxic*: teratogenic, carcinogenic
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Mustards are powerful vesicants, causing chemical burns, skin blistering, irritation, respiratory distress etc
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Mitosis Inhibitors
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Tubulin is the major protein forming the spindle – this is a dynamic structure with tubulins being added and removed in balance
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Stabilise the microtubule preventing it from depolymerisation – essential to allow chromosomes to pull apart so cells can’t enter metaphase stage of mitosis
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Show typical side effects, neuropathy, hair loss
Taxanes used in treatment of lung, ovarian and breast cancer
Side effects include nausea, pain, bleeding, fever, sore throat, dizziness
Hormone Derived Therapy
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1896: Beatson demonstrated that oopherectomy resulted in better prognosis in women with breast cancer
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A number of tumours are known to be dependent on hormone action e.g. breast, prostate, ovary, uterus and testicles
Oestrogen binds to the nuclear oestrogen receptor which dimerises and complexes with hormone response elements in the DNA sequences of hormone-inducible genes
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For oestrogen these are not only the genes involved female reproductive development but e.g. Lipid metabolism, coagulation factor synthesis, electrolyte balance
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Tamoxifen
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Tamoxifen is used to treat breast cancer and in breast tissue it is an oestrogen receptor antagonist
However it does not have as high an affinity as oestrogen does so it is necessary to remove endogenous sources of oestrogen
*In other tissues such bone and endometrium, tamoxifen has a partial agonist effect - due to presence of different co-regulators in these tissues
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Aromatase Inhibitors
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Third generation aromatase inhibitors such as Anastrazole and Letrozole are steroid based analogues of androstenedione – bind to substrate binding site on enzyme
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May be given to post-menopausal women after 2-3 years of Tamoxifen to complete 5 years of anti oestrogen therapy
Endocrine Therapy
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However, this leads to down regulation of GnRH receptors and LH release is inhibited
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Administration of anti-androgens e.g. Flutamide may help control the testosterone increase by inhibiting the androgen receptor
Gonadorelin Agonists e.g. goserelin, buserelin
Asparaginase
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Lymphoblasts in leukaemia do not have this enzyme and in these cells asparagine becomes an essential amino acid
As they cannot synthesise their own, these cells must pick up asparagine from the serum
Administration of asparaginase converts circulating asparagine to aspartate - depriving the tumour cell
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Side effects may include some mild bone marrow suppression, possible bleeding if synthesis of coagulation factors is affected, main problem is allergic reaction
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