Pharmacology - Cancer

Question 1

What is cancer?

Answer 1

Epigenetic disease resulting in the reprogramming of cancer cells so that they are growing in a no regulated manner and overcome physiological tissue and organ barriers (Invasive growth)

Question 2

What are the main 2 causes of cancer?

Answer 2

1) Germline mutations/hereditary familil syndromes (5-10%)

2) Environmental factors/somatic mutations (90-95%)

Question 3

What are the main risk factors of cancer?

Answer 3

1) Diet (35%) - (obesity (20%))
2) Smoking - 30%
3) Chronic infections (15-20%)
- Viruses 70%

Question 4

What cancers have the highest and lowest 5 year relative survival for men and women?

Answer 4

Men:
Highest 
> Testes 96%
> Hodgkin lymphoma 84%
Lowest
> Pancreas 3%
> Lung 6%

Women
Highest
> Melanoma 90%
> Hodgkin lymphoma 83%
Lowest
> Pancreas 2%
> Lung 6%`

Question 5

What is the major cancer treatment?

Answer 5

Surgical removal of the tumour if detected early enough

Question 6

What is radical mastectomy and when was it first indroduced?

Answer 6

surgical procedure in which the breast, underlying chest muscle (including pectoralis major and pectoralis minor), and lymph nodes of the axilla (armpit area) are removed as a treatment for breast cancer.
1894 to avoid cancer spread

Question 7

For how long did radical mastectomy remain a standard procedure?

Answer 7

> 70 years

Question 8

What therapy was introduced to replace radical mastectomy?

Answer 8

Removal of tumour mass plus chemo/radiotherapy

Equally effective but less morbidity

Question 9

How does untreatable cancer kill patients?

Answer 9

Primary tumour and/or metastases destroy essential tissue and organs

• wasting syndrome (20%): appetite loss, weight loss, weakness, fatigue, muscle atrophy
• Only 1 in 5 patients with metastasised disease will survive >5 years

Question 10

What percentage of cancer cures are achieved by which therapy?

Answer 10

• Systemic therapy (most common is chemotherapy) - 11%
• Local radiotherapy - 40%
• Surgery - 49%

Question 11

What limits the efficacy of anti-cancer therapies?

Answer 11

1) Drug concordance (patients need to take their drugs)
2) The therapeutic window is very small
3) Do not fully understand the action of anti cancer drugs
4) Complicated disease
5) Cancer cell populations are highly adaptable

Question 12

Why is the cancer therapeutic window so small?

Answer 12

Because cancer cells and normal diploid non maligant cells are so similar

• differences are in expression levels of genes but limited number of cancer specific mutations
• Result is that anti cancer drugs also have some non specific activity on normal cells

Question 13

Describe some factors that contribute to cancer complexity?

Answer 13

Every cancer is its own unique disease:

• Genetic factors differ
• Time point of cancer formation
• Time point of diagnosis
• The therapy

Metastases may require different treatment than the primary tumour
AND
Different cells from the same tumour may require different treatment

Question 14

How are cancer cells so highly adaptable?

Answer 14

They undergo clonal evolution by natural selection
Selection pressures include:
- hypoxia (oxygen deficiency)
- starvation
- Anti-cancer therapy
- different microenvironments (invasion of other tissues)

Question 15

What is the result of cancer cell adaptability?

Answer 15

Initially respond to treatment but eventually mutant resistant cells emerge and proliferate

Question 16

Name 7 common anti-cancer drug types

Answer 16

• Alkylating agents
• Platinum drugs
• Tubulin-binding agents
• Antimetabolites
• Topoisomerase inhibitors
• Cytotoxic antibiotics (extra reading)
• Monoclonal antibiotics (ER)

Question 17

What are akylating agents, how do they act and what are they used to treat? Give an example

Answer 17

Drugs regularly used in chemotherapy
React bases in DNA, and prevent cell division by cross linking the 2 strands on the double helix with an alkyl group
Used to treat Hodgkins lymphoma and other lymphoma laukaemias
Example drug: cyclophosphamide
chlorambucil

Question 18

What are platinum drugs, how do they act and what are they used to treat? Give examples

Answer 18

Platinum reacts with DNA bases (mainly guanine) resulting in intra and inter DNA strand cross linking
- Inhibits mitosis
- Induces DNA repair and subsequently cell death if the DNA damage is too severe
Examples:
- Cisplatin
- Carboplatin
- Oxaliplatin

Question 19

What are the 2 types of tubulin binding agents and what is their basic function?

Answer 19

Destabilising agents: bind to tubulin dimers and inhibit microtubule assembly
Stabilising agents: prevent microtubule disassembly , block mitosis

Question 20

What are the 2 types of destabilising tubulin-binding agents and what are they used to treat?

Answer 20

1) Vinca domain binders
- Vinca alkaloids (e.g vincristine, vinblastine) and Eribulin
- Used in chemotherapy to treat cancers by preventing mitosis
2) Colchicine domain binders
- Colchicine
- Used to treat gout

Question 21

What is the 1 type of stabilising tubulin-binding agent? Name the classes of drugs and individual examples?

Answer 21

Taxoid domain binders
- Drug classes: Taxanes (paclitaxel, docetaxel)
Epothilones (ixabepilone)

Question 22

What do antimetabolites do broadly?

Answer 22

Inhibit purine and pyrimidine synthesis, affecting DNA synthesis and therefore preventing DNA replication

Question 23

What is methotrexate and how does it function?

Answer 23

Antimetabolite - folic acid antagonist

Inhibits dihydrofolate resuctase in folate metabolism - folic acid needed for DNA synthesis

Question 24

What are nucleoside analogues and how do they work?

Answer 24

Antimetabolite
Contain nucleotide analogue, a sugar and 3 phosphates
Faulty nucleotides incorporated into chain, causing termination
e.g deoxycytidine

Question 25

What does topoisomerase I do?

Answer 25

Creates a single strand break during DNA replication, to relieve tension in the double stranded region to prevent supercoiling
- Also reseals the break

Question 26

What do topoisomerase I inhibitors do?

Answer 26

Inhibit topoisomerase I function resulting in inhibition of DNA replication
e.g topotecan

Question 27

What does topoisomerase II do?

Answer 27

Involved in reversing supercoiled DNA

- causes a double stranded break to allow another strand to pass through it, then reseals

Question 28

What do topoisomerase II inhibitors do?

Answer 28

Inhibit topoisomerase II, resulting in double stand breakages
e.g etoposide

Question 29

What are the 3 main types of targeted anti cancer drugs?

Answer 29

• Hormone therapy
• Kinase inhibitors
• Antibodies

Question 30

What is oestrogen receptor (ER) positive breast cancer

Answer 30

Breast cancers that rely on oestrogen to grow

Question 31

How is tamoxifen used to treat ER positive breast cancer?

Answer 31

Oestrogen receptor antagonist

• metabolised by cytochrome P450 in liver into active metabolites such as afimoxifen and endoxifen
• These have a much higher affinity for oestrogen receptors
• Competitive inhibition of oestrogen
• Tumour grows slows or stops due to lack of oestrogen

Question 32

What are the 3 main types of monoclonal antibodies used in cancer treatment?

Answer 32

Trastuzumab
Rituximab
Bevacizumab

Question 33

What does trastuzumab do and what cancer is it used to treat?

Answer 33

Targets human epidermal growth factor receptor 2 (HER2)

Used in treatment of breast cancer where there is overexpression of HER2

Question 34

what does rituximab do and what cancers is it used to treat?

Answer 34

Lyses B cell lymphocytes by attatching to a surface protein (CD20)
- used to treat B cell lymphomas

Question 35

What does Bevacizumab do and what cancer is it used to treat?

Answer 35

Inhibitor of vascular endothelial growth factor

Improves survival of patients with colorectal cancers