New Targets in Cancer Chemotherapy

Question 1

What position do alkylating agents preferentially alkylate?

Answer 1

Alkylating agents preferentially alkylate at the N7 position.

Question 2

What is a major carcinogenic lesion in DNA?

Answer 2

O6-alkyl guanine is a major carcinogenic lesion in DNA.

Question 3

What protein removes the adduct formed by alkylating agents?

Answer 3

The repair protein MGMT removes the adduct.

Question 4

Why is MGMT not considered a true enzyme?

Answer 4

MGMT is not a true enzyme as it is stoichiometric (1:1) and not regenerated; it’s a suicide enzyme.

Question 5

What does MGMT do to the methyl group?

Answer 5

MGMT removes the methyl group and returns to guanosine.

Question 6

What does repair with MGMT avoid?

Answer 6

Repair with MGMT avoids gene mutation, cell death, and tumorigenesis.

Question 7

What may cause resistance to Temozolomide in glioblastoma stem cells?

Answer 7

High levels of MGMT in glioblastoma stem cells may cause resistance to Temozolomide.

Question 8

What is the relationship between MGMT activity and tumor cell resistance?

Answer 8

There is a relationship between MGMT activity and resistance in tumor cells.

Question 9

How can resistance to O6-alkylators be overcome in preclinical models?

Answer 9

Resistance to O6-alkylators can be overcome by MGMT depletion.

Question 10

What is a potential strategy to enhance drug activity against tumors?

Answer 10

Knock out MGMT to potentiate the activity of other drugs.

Question 11

What is a potential downside of knocking out MGMT?

Answer 11

Myelosuppression is enhanced, so lower doses of alkylating agents would be required.

Question 12

What are the DNA repair pathways?

Answer 12

NHEJ, HR, SSBR, BER, NER, FA → repair different types of DNA damage.

Question 13

What is PAR?

Answer 13

Poly (ADP-ribose) is the 3rd nucleic acid in the mammalian cell, built from ADP-ribose units derived from NAD+.

Question 14

What is the structure of PAR?

Answer 14

PAR is a polyanionic polymer with a molecular weight that varies and can be linear or branched.

Question 15

Where is PARP-1 located?

Answer 15

PARP-1 is mainly located in the nuclei of cells and is abundant in most cells.

Question 16

What activates PARP-1?

Answer 16

PARP-1 is activated by DNA strand breaks.

Question 17

What is the function of PARP-1?

Answer 17

PARP-1 uses NAD⁺ to form PAR chains, which helps in DNA repair. Inhibition of PARP-1 prevents DNA repair and promotes cancer cell death.

Question 18

What is the first step in the role of PARP-1 in DNA repair?

Answer 18

PARP-1 is recruited to the site of damage.

Question 19

What does PARP-1 do at the site of damage?

Answer 19

PARP-1 builds a poly(ADP-ribose) chain onto the associated histone near the site of damage.

Question 20

What happens after PARP-1 modifies the histone?

Answer 20

The histone is removed from the DNA, allowing other enzymes and proteins to access and repair the DNA.

Question 21

What occurs after PARP-1 is removed?

Answer 21

PARP-1 builds a poly(ADP-ribose) chain on itself, starts self-modification, and is then removed.

Question 22

What is the role of PARG in DNA repair?

Answer 22

PARG cleaves the PAR chains from the histone and PARP-1.

Question 23

What happens after PARG cleaves the PAR chains?

Answer 23

The histone reattaches to its position with the DNA, and PARP-1 returns to being in soluble form.

Question 24

What do PARP inhibitors block?

Answer 24

PARP inhibitors block DNA repair.

Question 25

What effects do PARP inhibitors enhance?

Answer 25

PARP inhibitors enhance the effects of radiotherapy and chemotherapies.

Question 26

Which chemotherapies are enhanced by PARP inhibitors?

Answer 26

PARP inhibitors enhance the effects of alkylators and topoisomerase inhibitors.

Question 27

What are key drugs that are PARP inhibitors?

Answer 27

Key drugs include Olaparib, Rucaparib, Niraparib, Talazoparib, and Veliparib.

Question 28

Which PARP inhibitor was approved by the FDA in 2018?

Answer 28

Talazoparib was approved by the FDA in 2018 for metastatic breast cancer.

Question 29

What are PARP inhibitors designed as?

Answer 29

NAD⁺ mimics targeting PARP's NAD⁺ binding site.

Question 30

What modifications are preferred for PARP inhibitors?

Answer 30

Avoid electron-withdrawing groups (EWG) and prefer bulky groups for strong inhibition.

Question 31

How can amide conformation be controlled for selectivity in PARP inhibitors?

Answer 31

Lock part of the molecule by making it part of a ring.

Question 32

How can the ring be locked in place?

Answer 32

By hydrogen bonding and placing a second 5-membered ring.

Question 33

What role does nitrogen play in the structure of PARP inhibitors?

Answer 33

The nitrogen is able to hydrogen bond to that hydrogen.

Question 34

What do tumours need for growth?

Answer 34

Tumours need a supply of oxygen and other nutrients, which is facilitated by angiogenesis.

Question 35

What characterizes the vascular network in tumours?

Answer 35

Tumours have a poor vascular network that is disorganized, with vessel walls that are not well formed, leading to leaky vessels and high interstitial pressure.

Question 36

What happens to tumours larger than 1 mm in terms of oxygenation?

Answer 36

Tumours larger than 1 mm have poor oxygenation in the core, leading to different regions: oxic, hypoxic, and necrotic.

Question 37

What is the oxic region in a tumour?

Answer 37

The oxic region is well oxygenated, sensitive to radiotherapy and chemotherapy, and proliferating.

Question 38

Why is the oxic region sensitive to radiotherapy?

Answer 38

Radiotherapy relies on the presence of oxygen, as DNA damage often depends on oxygen being present to create free radicals.

Question 39

What is the hypoxic region in a tumour?

Answer 39

The hypoxic region has low oxygen (O₂) and is resistant to radiotherapy and chemotherapy.

Question 40

What is the necrotic region in a tumour?

Answer 40

The necrotic region consists of dead cells and cell debris, with no oxygen or nutrients.

Question 41

What are radiosensitizers?

Answer 41

Radiosensitizers, such as Etanidazole and pimonidazole, make hypoxic cells more sensitive to radiation by reducing glutathione and impairing defence mechanisms.

Question 42

What are hypoxia-selective prodrugs?

Answer 42

Hypoxia-selective prodrugs, like nitroimidazoles and mitomycin C, are activated under low oxygen conditions and are inactivated in normoxic cells.

Question 43

What functional groups are associated with hypoxia-selective prodrugs?

Answer 43

Functional groups associated with hypoxia-selective prodrugs include nitro, quinones, N-oxides, and transition metals.

Question 44

What is the role of oxygen as a radiosensitiser?

Answer 44

Oxygen is a potent chemical radiosensitiser that reflects extreme electron affinity, leading to DNA damage after absorbing energy from ionising radiation.

Question 45

What is hypoxia?

Answer 45

Hypoxia is a reduced level of oxygen, which has a knock-on effect of reducing the efficacy of radiation.

Question 46

How do oxygen-mimetic radiosensitisers work?

Answer 46

Oxygen-mimetic radiosensitisers work in hypoxic cells by replacing oxygen in the chemical reactions that lead to DNA damage.

Question 47

What is Etanidazole?

Answer 47

Etanidazole is a nitroimidazole drug with radiosensitising properties.

Question 48

How does Etanidazole affect glutathione concentration?

Answer 48

Etanidazole reduces glutathione concentration and inhibits GST, making tissues more sensitive to ionising radiation.

Question 49

What do hypoxic microenvironments contribute to?

Answer 49

Hypoxic microenvironments contribute to drug resistance and altered drug metabolism.

Question 50

What are prodrugs?

Answer 50

Prodrugs are drugs that are activated only in hypoxia via enzymatic reduction. ## Footnote Example: Mitomycin C