Lecture 16 Chemotherapy Targeting mitosis, transcription factors and signal transduction

Question 1

Give examples of steroid hormone sensitive cancers and the hormones they are associated with

Answer 1

breast cancer - oestrogen

prostate cancer - androgen

Question 2

What is meant by the term ‘hormone responsive’ cancer

Answer 2

Giving hormone treatment regresses the cancer

Question 3

What is meant by the term ‘hormone dependent’ cancer

Answer 3

Removing/inhibiting the hormone regresses the cancer

Question 4

What is meant when it is said that the hormones requires ‘intracellular cytoplasmic receptors’?

Answer 4

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

Question 5

Explain how tamoxifen works

Answer 5

Tamoxifen is structurally similar to oestrogen - competitively binds to the oestrogen receptors to block the activation of transcription factors and therefore limits cellular growth

Question 6

Why should tamoxifen only be given for a limited period of time?

Answer 6

acts as a weak oestrogen and could possibly stimulate precancerous lesions
Therefore should only be used for up to around 5 years

Question 7

What is tamoxifen often combined with if given to pre-menopausal woman?

Answer 7

leuprolide i.e. gonadotropin-releasing hormone, GnRH, analogue - all involved in the production of oestrogen

Question 8

in what form is tamoxifen given?

Answer 8

oral

Question 9

How is tamoxifen excreted?

Answer 9

bile

faeces

Question 10

Explain why aromatase inhibitors are needed and how they work

Answer 10

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

Question 11

Name examples of aromatase inhibitors

Answer 11

Anastrozole

Letrozole

Question 12

In what form are aromatase inhibitors given?

Answer 12

oral

Question 13

How are aromatase inhibitors metabolised?

Answer 13

liver

Question 14

Name examples of non steriodal anti-androgen drugs

Answer 14

Flutamide
Nilutamide
Bicalutimide

Question 15

How do anti-androgen drugs work and which cancer is it used to treat?

Answer 15

competitively binds with androgens to the androgen receptor

Works for androgen +ve prostatic cancers

Question 16

Explain the function of the EGF receptor and its link to breast and lung cancer

Answer 16

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

Question 17

What are the brand names of specific tyrosine kinase inhibitors

Answer 17

Iressa

Tarceva

Question 18

Explain what the BCR-ABL protein is

Answer 18

produced due to chromosomal translocation i.e. swapping of different parts of chromosomes
This protein has tyrosine kinase activity therefore can activate cell proliferation

Question 19

In what cancer is the BCR-ABL protein specific for?

Answer 19

chronic myelogenous leukaemia

Question 20

Name the inhibitor of BCR-ABL and its success

Answer 20

Gleevec (brand) or Imatinib

96% of patients result in remission

Question 21

In what form is Gleevec/Imatinib given?

Answer 21

Oral

Question 22

How is Gleevec/Imatinib excreted?

Answer 22

faecally

Question 23

Which tumour suppressor gene is mutated in around 50% of human cancers?

Answer 23

P53

Question 24

P53 forms a protein protein complex with what in cancer cells to degrade P53

Answer 24

MDM2 oncogene

Attaches ubiquitin to P53

Question 25

What are nutlins and how do they work?

Answer 25

Nutlins and small molecules that bind to MDM2 and release P53
This is activated to mediate growth arrest/apoptosis of cancer cells

Question 26

Name the difficulty in using molecules to inhibit protein:protein complexes

Answer 26

Difficult due to strong bond between them

Question 27

What is the function of B-raf and why is inhibitors of B-raf used in cancers?

Answer 27

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

Question 28

Name a B-raf inhibitor and its uses

Answer 28

Nexavar
Approved for renal cancer
Also has tyrosine kinases = wider anti cancer applications

Question 29

How have B-raf inhibitor become resistant in some patients with melenoma?

Answer 29

mutation can occur in proteins that regulate phosphorylation upstream of B-raf (see pathway)