Pathophysiology of Cancer

Question 1

What are the two main differences between benign and malignant tumours?

Answer 1

Benign are not invasive, and cannot metastasize

Question 2

What are the four steps of the cancer process?

Answer 2

1. Initiated cell - a mutation in a single cell
2. Promotion - initiated cell proliferation rate is high
3. Malignant conversion - there is a critical, irreversible mutation
4. Progression - progeny continue to mutate

Question 3

What are the eight capabilities cancer needs to become invasive?

Answer 3

1. Self-sufficient in growth
2. Insensitive to growth
3. Can evade apoptosis
4. Can proliferate indefinitely
5. Have angiogenesis
6. Can metastasize and invade
7. Have cellular energy deregulation
8. Can avoid the immune system

Question 4

What are common mutations to produce self-sufficiency in growth?

Answer 4

Oncogene activation to produce a tumours own growth system are often results of mutations in autocrine GF production, and over-expression of GF receptors.
Mutations in the tyrosine kinase signal transduction pathways can also lead to uncontrolled proliferation

Question 5

What are common mutations for a tumour cell to become insensitive to growth inhibition?

Answer 5

These are often loss of function mutations in tumour suppressor genes i.e. the Rb pathway (pathway that extracellular anti-proliferative signals)

Question 6

What are common mutations in cancer that allow them to evade apoptosis?

Answer 6

1. Increased hormone receptor expression increasing survival signal
2. Increased anti-apoptotic protein expression
3. Most common is they have a mutation in P53 tumour suppressor gene, inactivating it

Question 7

What is the main mutation that creates cell immortalisation in tumours?

Answer 7

80-90% have increased telomerase expression, the enzyme that transcribes telomere repeats. This is another mechanism to prevent apoptosis

Question 8

How do tumours become able to perform angiogenesis?

Answer 8

There is a shift in the balance of positive and negative signalling proteins involved in angiogenesis/neovascularization
(about as much as we need to know)

Question 9

How do tumours evade the immune system?

Answer 9

They co-opt it, and use it to increase growth and encourage invasion

Question 10

How does inherited Lynch syndrome contribute to cancer development?

Answer 10

Via a mutation in DNA repair genes (MSH2, MLH1, MSH6)

Question 11

How does inherited Li-Fraumeni syndrome contribute to development of cancer?

Answer 11

A pre-existing mutation in TP53, a tumour suppressor gene

Question 12

In which cancers are the DNA repair genes BRCA1 and BRCA2 implicated in?

Answer 12

Breast and ovarian cancers

Question 13

Is chemotherapy usually used in conjunction with other treatments?

Answer 13

Yes

Question 14

What are three ways in which chemotherapy is used in conjunction with other treatments of cancer?

Answer 14

1. Neoadjuvant - before surgery to shrink the tumour
2. Induction - given to reduce remission, common with leukemia
3. Definitive - to cure, mainly in early stage tumours that are chemo-sensitive

Question 15

What are the 6 principles of Chemotherapy?

Answer 15

1. Specificity of cancer drugs
2. Kinetics of tumour growth and detection
3. Drug efficacy and fixed proportion killing
4. Drug efficacy and tumour regrowth
5. Cell cycle and susceptibility to specific drugs
6. Drug resistance

Question 16

What are mechanisms of traditional chemotherapy drugs?

Answer 16

They are anti-proliferative and decrease tumour growth

Question 17

What must a cancer drug have a kill % greater than, to effectively kill a tumour?

Answer 17

A drugs kill % must be greater than the cell number

E.G. a 99.999% kill rate will be effective with a tumour with

Question 18

Following initial treatment, what are the three possible situations a tumour may be in?

Answer 18

1. Killed by the immune system’s CD8+ T-cells leading to a cure
2. Still actively growing AKA residual disease eventually leading to reappearance
3. Becoming dormant for many years before reactivation

Question 19

What is the classic mechanism of anti-cancer drugs, and give four examples of how they accomplish this
(Hint - one example is impaired synthesis of DNA bases)

Answer 19

Many anticancer drugs interfere with DNA synthesis and/or function, inducing apoptosis AKA cell death
Mechanisms:
1. Chemical damage to DNA
2. Impaired synthesis of DNA bases
3. Inhibition of transcription/translation
4. Disruption of cell division mechanisms

Question 20

What is the mechanism of alkylating agents, and give an example of an alkyating agent?

Answer 20

Alkylating DNA at guanine bases (usually) to form DNA adducts, leading to strand breaks and cell death independent of the cell cycle
Examples: Nitrogen mustards, nitrosoureas

Question 21

Which class of anticancer drugs are platinum-based drugs similiar to? Give an example of a platinum-based drug

Answer 21

Alkylating agents

Example - Cisplatin

Question 22

What are two groups of the anticancer drugs Anti-metabolites, which phase of the cell cycle do these affect, and give an example of each type

Answer 22

-Folic acid antagonists i.e. Methotrexate
- DNA base analogues i.e. 5-Fluorouracil
This affect the S phase of the cell cycle

Question 23

What are two groups of mitotic inhibitors?

Answer 23

• Those that interfere with the mitotic spindles

- Those that bind to microtubules to prevent their disassembly in mitosis

Question 24

What are two groups of cytotoxic antibodies used to treat cancer?

Answer 24

1. Anthracyclines, which inhibit topoisomerase

2. Bleomycins, which induce single and double DNA strand breaks

Question 25

What type of anticancer drug is Tamoxifen, often used to treat breast cancer?

Answer 25

It’s a hormone based drug - it blocks estrogen receptors

Question 26

What is a non-cell cycle phase dependent anticancer drug?

Answer 26

Alkylating agents

Question 27

What are likely side effects of classical cancer drugs?

Answer 27

• GI: mouth ulcers, nausea (esp. alkylating agents), vomiting
• Hair loss (esp cyclophosphamide & platinum drugs)
• Myelosuppression (esp anti-metabolites & mitotic inhibitors)

Question 28

How are newer targeted drugs for cancer different to classical ones?

Answer 28

• They are gentler and more specific
• Are in large part, tyrosine kinase inhibitors
• Can also be antibodies which attempt to block angiogenesis in tumours

Question 29

How are newer chemotherapy drugs administered?

Answer 29

With classical ones

Question 30

What is the biggest problem with newer anti-cancer drugs?

Answer 30

Resistance to the tyrosine kinase inhibitors - can develop within 6-7 months

Question 31

What are some mechanisms of resistance to anticancer drugs?

Answer 31

1. Lower activation of metabolism-dependent drugs
2. Increased metabolic inactivation of toxic drugs
3. decreased accumulation of drugs due to reduced uptake or increased efflux

Question 32

How does radiotherapy work?

Answer 32

1. Damages DNA and induces apoptosis

2. Ionizes water and increases production of free radicals to kill the cancer

Question 33

Which cancer drugs cause:
Skin Pigmentation
Neurotoxicity
Pulmonary fibrosis
Cardiomyopathy

Answer 33

• 5-fluorouracil
• Mitotic inhibitors and Cisplatin (platinum based)
• Bleomycin
• Anthracyclines