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Anti-cancer Agents (Hormone Therapy (TAMOXIFEN (Selective estrogen…
Anti-cancer Agents
Hormone Therapy
Tumours from the hormone sensitive tissues will have steroid receptors and the number of steroid receptors suggests the efficacy of the hormone treatment. The number of receptors can be determined by biopsy.
Both hormone therapy and cytotoxic therapy are equally effective but hormone therapy would be BETTER TOLERATED in hormone sensitive tumours.
Tumour Growth Inhibition
- Hormones with opposing actions such as glucocorticoids inhibit lymphocyte proliferation so they can be used in the treatment of leukemia and lymphomas
- Hormone antagonists which are hormone analogues which bind to the receptors and blocks the action. TAMOXIFEN- Anti-oestrogen and FLUTAMIDE- Anti-androgen
- Agents inhibiting synthesis of specific hormones. Aromatase Inhibitors
TAMOXIFEN
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Antagonist at the oestrogen receptors in the breast but acts as a partial agonist at the oestrogen receptors in the uterus and bone
In early and advanced estrogen receptor positive breast cancers in both pre and post menopausal women
MOA- Prodrug is converted to the active metabolite 4-hydroxytamoxifen. It enters the cell by passive diffusion and binds to the estrogen receptor which is an intracellular receptor. It is then dimerisation occurs so the recruitment of co-factors is prevents. It is translocated into the nucleus. In the nucleus it binds to the ERE but the transcription of the oestrogen responsive genes is prevented. It interferes with the recycling of the receptors as the complex does not readily dissociate.
The oestrogen receptor has 2 transcriptional domains- AF1 and AF2 which recruit the co-activator proteins. AF1 is in charge for activity in bone and the uterus while AF2 is responsible for breast tissue. Tamoxifen blocks the effects of AF2 by competitively binding to it (so tamoxifen acts as an antagonist in the breast tissue) but the effects of AF1 are not inhibited as it just acts as a partial agonist in those tissues.
Adverse Effects- Hot flushes, irregular menstrual cycles, vaginal discharge
AROMATASE INHIBITORS
The enzyme is used in converting testosterone to estradiol in the ovaries and to convert androstenedione to estrone in adipose tissue.
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Classes: Steroid analogues of androstenedione which irreversible inhibits aromatase enzymes. (E.g- EXEMESTANE). Non-steroidal inhibitors which acts reversibly for the androstenedione binding site on the aromatase enzyme. (E.g- LETROZOLE, ANASTROZOLE)
Used to treat oestrogen postive breast and ovarian cancers in post-menopausal women. When they are used in premenopausal women, they are combined with surgical and medical ovarian ablation.
Targeted Therapy
These are less toxic forms which are more specific to each type of cancer. Causes disease stabilisation and further tumour growth is prevented.
Receptor over-expression
Normal cells have two copies of the HER 2 gene which produces HEGF- human epidermal growth factor. The HER 2 gene is responsible for the transmission of signals which allows for controlled cell growth with regulated rate of cell division. During over expression of the HER 2 gene, there will be an excessive amount of the HER 2 protein. Growth promoting signals will be transmitted continuously and the rate of cell division will increase.
When a normal cell has two copies of the HER 2 gene, a tumour cell will have multiple copies of the HER 2 gene due to gene amplification. The HER 2 gene can be detected by FISH and immunohistochemical analysis of HER 2 protein over expression
TRASTUZUMAB- Monoclonal antibody against HER 2 which binds to the HER 2/receptor dimerization and acts by ADCC and flags the tumour cells for destruction by the body's immune system. Proliferation of the cancer cells which over-express the HER 2 receptor is also inhibited. Expensive. Associated with cardiac dysfunction.
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Angiogenesis Inhibition
Involves the inhibition of the growth of new blood vessels in tumours by blocking the angiogenesis signalling cascade and by blocking endothelial cell proliferation.
Angiogenesis signalling pathways are blocked by small molecules tyrosine kinase inhibitors such as SUNITINIB and by neutralising antibodies to growth factors such as anti-VEGF, BEVACIZUMAB which binds and neutralizes VEGF blocking its binding to the VEGF receptor
Classical Chemotherapy
Contraindications- Presence of active infection, Depression of existing bone marrow and very advanced disease
Limitations- Lack of selectivity (so even normal proliferating cells will be affect- MOA of cytotoxic agents), lack of sensitivity (so high doses may need to be used but this can damage the kidneys), development of resistance, complete elimination of the tumour may not be possible and most of the treatments target cell proliferation and not metastasis or invasion
Other Treatments
Signal transduction inhibitors, gene expression modulators, apoptosis inducers, immunotherapy, targeting cancer stem cells and monoclonal antibody conjugates.