MDT - Newer Targets

Question 1

Radiotherapy results in what types of DNA lesions?

Answer 1

SS-breaks, DS-breaks, Damage to bases. Only effective in presence of O2.

Bleomycin: DNA cleavage by bleomycin depends on oxygen and metal ions, at least in vitro.

Major repair pathways for radiotherapy: NHEJ, SSBR, BER (base excision repair) + homologous recombination (HR).

Question 2

Mono-alkylators, such as alkylsulfonates, nitroso-ureas and temozolomide cause what type of damage to DNA?

Answer 2

Damage to bases + Bulky adducts.

Major repair pathways: BER, HR, NER, ENDO, FA.

Question 3

Radiotherapy and the use of bleomycin is only effective at targeting tumour cells with what?

Answer 3

O2 molecules present (+metal ions for bleomycin).

Question 4

Alkylsulfonates, nitroso-ureas and temozolomide are examples of what?

Answer 4

Mono-alkylators. Cause damage to bases, bulky adducts.

Question 5

What are the major repair pathways for damage cause by radiotherapy/bleomycin?

Answer 5

NHEJ, SSBR, BER, HR.

Question 6

What are the major repair pathways of mono-alkylators?

Answer 6

BER, HR, NER, ENDO, FA

Question 7

Type of therapy that causes SS-breaks, DS-breaks and damage to bases

Answer 7

Radiotherapy/ bleomycin. NHEJ, SSBR, BER, HR

Question 8

N-Mustards, Mitomycin C and platinum drugs such as cisplatin/carboplatin are examples of what class of DNA damaging chemotherapeutic?

Answer 8

Cross-linkers. They cause DS-breaks, Damage to bases and the formation of bulky adducts. MRPs: HR, FA, ENDO, NER.

Question 9

Camptothecins and etoposide have what in common?

Answer 9

They are both topoisomerase inhibitors which cause SS breaks and DS breaks. The normal function of topoisomerase is to take the twists out of DNA. They can relax DNA by breaking one strand, allowing the other stand to pass through and then rejoining the original strand. Camptothecins etc. allow topoisomerases to break the DNA strand but don’t allow them to rejoin: causing single strand breaks. DS-breaks occur when SS-breaks occur in close proximity to each other.

Question 10

What is the MOA of Cross-linkers such as N-Mustards, Mitomycin C and platinum drugs?

Answer 10

They cause DS-breaks, damage the bases and cause the formation of bulky adducts.
MRPs: HR, FA, ENDO, NER

Question 11

Topoisomerase inhibitors, such as ____________ and ___________, cause what damage to DNA?

Answer 11

Camptothecins and etoposide, are both topoisomerase inhibitors which cause SS breaks and DS breaks. The normal function of topoisomerase is to take the twists out of DNA. They can relax DNA by breaking one strand, allowing the other stand to pass through and then rejoining the original strand. Camptothecins etc. allow topoisomerases to break the DNA strand but don’t allow them to rejoin: causing single strand breaks. DS-breaks occur when SS-breaks occur in close proximity to each other.

Question 12

Aphidicolin and hydroxyurea are examples of which class of DNA-damaging therapy which can cause DS-breaks?

Answer 12

Replication inhibitors.

Question 13

How do topoisomerase inhibitors cause DS-breaks?

Answer 13

Camptothecins and etoposide, are both topoisomerase inhibitors which cause SS breaks and DS breaks. The normal function of topoisomerase is to take the twists out of DNA. They can relax DNA by breaking one strand, allowing the other stand to pass through and then rejoining the original strand. Camptothecins etc. allow topoisomerases to break the DNA strand but don’t allow them to rejoin: causing single strand breaks. DS-breaks occur when SS-breaks occur in close proximity to each other.

Question 14

How is the damage caused by replication inhibitors repaired? What are two examples of replication inhibitors?

Answer 14

HR, FA, NHEJ, ENDO. Two examples of replication inhibitors: Alphidicolin, hydroxyurea.

Question 15

How is the damage caused by topoisomerase inhibitors repaired?

Answer 15

FA, HR, ENDO, SSBR, NHEJ

Question 16

How do antimetabolites such as 5-FU and thiopurines cause DNA damage?

Answer 16

They damage the bases themselves, repaired using BER.

Question 17

The potentiation of DNA-damaging therapies occurs via what? [2]

Answer 17

Number 1: Direct inhibition of a repair ‘enzyme’ – MGMT is inhibited by 06-benzylguanine/patrin.

Number 2: Inhibition of a control system/series of repair mechanisms -this is a more useful way. PARP-1 inhibitors: Olaparib + Veliparib. Checkpoint Kinase (CHK) inhibited by XL844. DNA-dependent protein kinase (DNAPK).

Question 18

Olaparib and Veliparib inhibit the action of what?

Answer 18

The PARP-1 repair control system.

Question 19

XL844 inhibits

Answer 19

Checkpoint kinase (CHK) – results in continued damage accumulation in DNA.

Question 20

NU7441 is an inhibitor of

Answer 20

DNA-dependent protein kinase (DNAPK)

Question 21

Patrin inhibits the action of which DNA repair enzyme?

Answer 21

MGMT

Question 22

Inhibitor of CHK (Checkpoint Kinase)

Answer 22

XL844

Question 23

06-benzylguanine inhibits the action of which DNA repair enzyme?

Answer 23

MGMT

Question 24

How does tumour physiology differ from that of healthy tissues?

Answer 24

Poor vascular structure: dispersed network, vessel walls not well formed, leaky, high interstitial pressure.

Outermost layer: Oxic region – well oxygenated, proliferating, sensitive to radiotherapy and chemotherapy.

Middle layer: Hypoxic region – low oxygen concentration, not proliferating. Relatively insensitive to radiotherapy and chemotherapy. Radiotherapy: this needs oxygen to work, Chemotherapy: this needs cells to be actively dividing as it targets DNA replication.

Innermost layer: necrotic region – dead cells and cell debris.

Question 25

Why is the outermost layer of a tumour mass susceptible to radiotherapy and chemotherapy?

Answer 25

The cells have a good supply of nutrients/oxygen which is needed for radiotherapy to work, plus these are required for the cell to be able to proliferate and chemo only targets proliferate cells – DNA damaging drugs.

Question 26

Why is the middle layer of a tumour mass able to resist chemo/radiotherapy?

Answer 26

Low amounts of nutrients/o2 = not proliferating – just surviving, chemo only works against proliferating cells and radio only works in presence of oxygen in the tumour cells.

Question 27

Why do we need to develop ways of targeting the middle layer of non-proliferating, low O2 content tumour mass cells?

Answer 27

The radio/chemo can succeed in killing the outermost layer of tumour cells but this leave the hypoxic region cells behind and they can then cause recurrence of the cancer.

Question 28

Why may it be possible to develop drugs targeted at the hypoxic region of tumour masses that have less off-target effects than current therapies?

Answer 28

Most normal tissues do not have hypoxic regions. If we could develop a molecule which only becomes activated in hypoxic regions….

Question 29

Because hypoxic tumour tissue is less sensitive to radiotherapy, drugs such as pimonidazole and etanidazole were developed. What is their purpose?

Answer 29

They are electron-affinity radiosensitisers. Etanidazole is a nitroimidazole drug used for its radiosensitizing properties. Administration of etanidazole results in a decrease of glutathione concentration and inhibits glutathione S-transferase.

Question 30

What is the EPR effect and how can this be taken advantage in cancer treatment?

Answer 30

There is no effective lymphatic drainage in solid tumours. The soluble polymeric prodrugs accumulate in solid tumours – can use this to target tumours. Cytotoxic drugs which are attached to a polymer, leak out of the vasculature of tumour and there is no effective drainage system in place to remove them so they accumulate up to cell killing levels.

Question 31

Nitroimidazoles, Mitomycin C and Tirapazamine are examples of:

Answer 31

Hypoxia-selective drugs.

Question 32

What is the MOA of hypoxia-activated prodrugs, such as nitro compounds, N-oxides, quinones and metal complexes?

Answer 32

They are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins.

Question 33

What is the rationale behind using angiogenesis inhibitors?

Answer 33

Stop the growth of new blood vessels: Stop the growth of a small tumour into a large tumour.

Question 34

What does VEGF stand for?

Answer 34

Vascular Endothelial Growth Factor

Question 35

What dose PDGF stand for?

Answer 35

Platelet-Derived Growth Factor

Question 36

What do VEGF and PDGF have in common?

Answer 36

Both are signals for angiogenesis.

Both activate kinase systems.

Question 37

What is Sunitinib? How does it inhibit angiogenesis?

Answer 37

It inhibits both VEGFR and PDGFR. Approved in 2006 for renal carcinomas and GIST.

Question 38

Avastin is an antibody for _____ that was approved in 2004 for colon carcinoma. How does it work?

Answer 38

Prevents angiogenesis by blocking the VEGF pro-angiogenesis signalling pathway.

Question 39

What is an example of an inhibitor of kinase activity that was approved in 2006 for renal carcinomas and GIST? What kinases does it inhibit?

Answer 39

Sunitinib inhibits both VEGFR and PDGFR. Both are signalling pathways promoting the growth of new blood vessels.

Question 40

What are some examples of hypoxia-selected drugs?

Answer 40

Nitroimidazoles
Mitomycin C
Turapazamine
AQ4N

Question 41

What is a neutralising antibody for the VEGFR that was approved in 2004 for colon carcinoma?

Answer 41

Avastin/Bevacizumab.