Cancer Chemistry

Question 1

What is the most important target out of the 4 bases for anti cancer therapies?

Answer 1

N7 atom of guanine

Question 2

What happens when the N7 atom of guanine is alkylated?

Answer 2

It becomes positively charged and the charge is stabilised by resonance

Question 3

What are DNA lesions?

Answer 3

They are chemically altered bases which can be caused by Reactive oxygen species, radiations or chemicals and also spontaneous

Question 4

What is the difference between a monofunctional and a bifunctional akylating agent?

Answer 4

point mutations versus major deletions DNA strand breakage and hyper recombination

Question 5

What is the difference between an intrastrand, and an interstrand, cross-link?

Answer 5

Intrastrand is within a strand and interstrand is between opposite strands

Question 6

Why are interstrand cross links particularly cytotoxic?

Answer 6

Prevent replication and transcription by preventing the parting of two DNA strands

Question 7

What is the difference between mutagenic and clastogenic agents?

Answer 7

Clastogenic are those that can cause damage on a chromasomal level rather than DNA level.

Question 8

Nitrogen mustards don’t always form bisadducts. What side reaction can occur, resulting in the formation of monoadducts?

Answer 8

n N7-alkylated guanine derivative (11) as shown in Figure 6. This guanine monoadduct can then form another reactive aziridinium intermediate, which can react either with water to form a 2-hydroxyethyl monoadduct

Question 9

Interstrand cross-links formed by nitrogen mustards distort the DNA structure, e.g. they may bend it. Can you explain why?

Answer 9

The minimal distance between the guanines in this sequence is approximately 6.8 Å in B-form DNA, which is more than the 5.1 Å distance that can be spanned by the five atoms that comprise the cross-link

Question 10

Why technically speaking is the phosphoramide group not an alkylating agent?

Answer 10

Because the phosphoramide electron withdrawing group means the nitrogen lone pair is not available for formation of the azridinium ion

Question 11

Why is phosphoramide mustard an active alklating agent, when cyclophosphamide is not?

Answer 11

Because the phosphoramide group is less electron-withdrawing

Question 12

How do anthacyclines work?

Answer 12

Instead they interact non-covalently with the DNA.

The planar anthracycline rings insert between the planes of successive base pairs – a process called intercalation.

Question 13

“Many cytotoxic antibiotics act as radiomimetics and simultanous use of radiotherapy should be avoided because it may markedly increase toxicity”

Why?

Answer 13

Both produce similar modes of action and can effect healthy cells if over concentrated

Question 14

Which pathways are primarily used for the repair of double strand breaks?

Answer 14

Homologous recombination

Non-homologous end joining

Question 15

How does ionising radiation cause DNA damage? Which of the following statements are true in relation to IR induced DNA damage?

Answer 15

Reactive oxygen species (ROS) are produced which react with DNA
Bases are modified (e.g. 8-OxoG)
Double strand DNA breaks occur
Single strand DNA breaks occur

Question 16

Temozolomide (TMZ) doesn’t directly cause double strand DNA breaks, however lethal DSBs result from the futile attempts of the cell to repair TMZ induced DNA damage. What type of DNA lesion does TMZ cause that ultimately results in DSBs?

Answer 16

Methylation

Question 17

Which DDR (DNA damage repair) pathway is required for these DSBs (double stranded breaks) to result?

Answer 17

MMR DNA mismatch repair

Question 18

Which protein has been identified as being involved in TMZ resistance, and also as a target for potentiation of TMZ (albeit with unacceptable side effects)?

Answer 18

MGMT O6-methylguanine DNA methyltransferase

Question 19

The paper discusses the targeting of proteins involved in double strand repair as a strategy for increasing the sensitivity of cancers to radiotherapy.
a. Which protein required for HR is suggested as a target for radiosensitization?

Answer 19

ATM

Question 20

The paper discusses the targeting of proteins involved in double strand repair as a strategy for increasing the sensitivity of cancers to radiotherapy.
b. Which protein required for NHEJ is suggested as a target for radiosensitization?

Answer 20

DNA-PK

Question 21

The paper discusses the targeting of proteins involved in double strand repair as a strategy for increasing the sensitivity of cancers to radiotherapy.
c. Which checkpoint signalling protein is suggested as a target for radiosensitization?

Answer 21

Chk-1

Question 22

Topoisomerase inhibitors cause DNA breaks by preventing the religation of DNA during conformational reorganisation.
Which out of camptothecin or etoposide would you expect to be more toxic to a slowly proliferating cancer?

Answer 22

Etoposide

Question 23

Which of the following DDR pathways are involved in repair of intrastrand crosslinks?

Answer 23

NER

Question 24

What condition can be exploited to kill cancer cells in which one DDR pathway is lacking (for example due to mutation)?

Answer 24

Synthetic lethality