Lecture 16 Chemotherapy Targeting mitosis, transcription factors and signal transduction Flashcards
Give examples of steroid hormone sensitive cancers and the hormones they are associated with
breast cancer - oestrogen
prostate cancer - androgen
What is meant by the term ‘hormone responsive’ cancer
Giving hormone treatment regresses the cancer
What is meant by the term ‘hormone dependent’ cancer
Removing/inhibiting the hormone regresses the cancer
What is meant when it is said that the hormones requires ‘intracellular cytoplasmic receptors’?
Hormone must bind to the intracellular cytoplasmic receptors which are transcriptional factors
When bound, activation of the transcriptional factors occurs and bind to chromatin, upregulating genes for cellular growth
Explain how tamoxifen works
Tamoxifen is structurally similar to oestrogen - competitively binds to the oestrogen receptors to block the activation of transcription factors and therefore limits cellular growth
Why should tamoxifen only be given for a limited period of time?
acts as a weak oestrogen and could possibly stimulate precancerous lesions
Therefore should only be used for up to around 5 years
What is tamoxifen often combined with if given to pre-menopausal woman?
leuprolide i.e. gonadotropin-releasing hormone, GnRH, analogue - all involved in the production of oestrogen
in what form is tamoxifen given?
oral
How is tamoxifen excreted?
bile
faeces
Explain why aromatase inhibitors are needed and how they work
in post menopausal woman, peripheral synthesis of oestrogen can occur e.g. liver, fat etc. - caused by the enzyme aromatase
Therefore if inhibitors of aromatase is given this oestrogen production can be limited
Name examples of aromatase inhibitors
Anastrozole
Letrozole
In what form are aromatase inhibitors given?
oral
How are aromatase inhibitors metabolised?
liver
Name examples of non steriodal anti-androgen drugs
Flutamide
Nilutamide
Bicalutimide
How do anti-androgen drugs work and which cancer is it used to treat?
competitively binds with androgens to the androgen receptor
Works for androgen +ve prostatic cancers
Explain the function of the EGF receptor and its link to breast and lung cancer
EGF = epidermal growth hormone
It is a intracellular tyrosine kinase domain protein
When activated, tyrosine is phosphorylated and activation of the signal transduction cascade and cell proliferation occurs
Oncogene versions of EGF present in lung or breast cancers - either overexpression or mutated e.g. constitutive active
What are the brand names of specific tyrosine kinase inhibitors
Iressa
Tarceva
Explain what the BCR-ABL protein is
produced due to chromosomal translocation i.e. swapping of different parts of chromosomes
This protein has tyrosine kinase activity therefore can activate cell proliferation
In what cancer is the BCR-ABL protein specific for?
chronic myelogenous leukaemia
Name the inhibitor of BCR-ABL and its success
Gleevec (brand) or Imatinib
96% of patients result in remission
In what form is Gleevec/Imatinib given?
Oral
How is Gleevec/Imatinib excreted?
faecally
Which tumour suppressor gene is mutated in around 50% of human cancers?
P53
P53 forms a protein protein complex with what in cancer cells to degrade P53
MDM2 oncogene
Attaches ubiquitin to P53
What are nutlins and how do they work?
Nutlins and small molecules that bind to MDM2 and release P53
This is activated to mediate growth arrest/apoptosis of cancer cells
Name the difficulty in using molecules to inhibit protein:protein complexes
Difficult due to strong bond between them
What is the function of B-raf and why is inhibitors of B-raf used in cancers?
Growth factor binds to receptors = activation of tyrosine kinases = phosphorylation of B-raf = phosphorylation of P90 = phosphorylation of transcription factors = binds and activates genes related to apoptosis
Name a B-raf inhibitor and its uses
Nexavar
Approved for renal cancer
Also has tyrosine kinases = wider anti cancer applications
How have B-raf inhibitor become resistant in some patients with melenoma?
mutation can occur in proteins that regulate phosphorylation upstream of B-raf (see pathway)
