Anticancer drugs

Question 1

Which anticancer drugs bind covalently to DNA?

Answer 1

1. Nitrogen mustards
2. Nitrosureas
3. Aziridines
4. Platinum compounds

Question 2

How do nitrogen mustards produce their effect?

Answer 2

Covalently link an alkyl group to chemical moieties in nucleic acids and proteins

Question 3

What side chains does nitrogen mustard have?

Answer 3

Two chloroethyl side chains

Question 4

How does nitrogen mustard attack guanine?

Answer 4

One of the side chains undergoes cyclisation and forms an immonium ion intermediate, which is highly reactive and attacks the N7 group of guanine

Question 5

What is the result of nitrogen mustard covalently binding to guanine?

Answer 5

1. Cross-link between DNA strands
2. Cross-link between bases in same strand
3. Inhibition of DNA replication and gene transcription

Question 6

What happens if the second nitrogen mustard side chain reacts with H2O instead of another guanine?

Answer 6

Monoalkylated guanine is produced

Question 7

What does monoalkylated guanine do?

Answer 7

Forms an anomalous base pair with thymine

Question 8

How do nitrogen mustards cause strand scission?

Answer 8

1. Monoalkylated guanine is recognised by DNA repair systems

2. Strand scission occurs when cell attempts to repair alkylated DNA

Question 9

Which side reactions of nitrogen mustards contribute to the general toxicity of these drugs?

Answer 9

Reactions with other nucleophilic groups in DNA, RNA and protein

Question 10

What is phenylalanine a precursor of?

Answer 10

Melanin

Question 11

Where does melphalan accumulate?

Answer 11

Melanomas

Question 12

What side chain do nitrosureas have?

Answer 12

Chloroethyl side chain (at least one)

Question 13

What groups do nitrosureas covalently add?

Answer 13

Alkyl or carbamoyl moieties

Question 14

What are the preferred sites of attack of nitrosureas?

Answer 14

N7 and O6 positions of guanine

Question 15

How is mitomycin C activated?

Answer 15

Chemical or enzymatic reduction of the quinone group

Question 16

What is the principal coordinate of cisplatin action?

Answer 16

Intra-strand cross-link formed by the binding of the drug to two neighbouring guanines

Question 17

What is cisplatin-induced intrastrand cross-linking thought to induce?

Answer 17

Major bending of DNA duplex towards major groove

Question 18

How does cisplatin inhibit DNA replication?

Answer 18

1. Major bending of DNA duplex towards major groove
2. Physical block provided by platinum adduct on template strand
3. Inhibits DNA polymerases

Question 19

How do anthracyclines kill tumour cells?

Answer 19

1. Intercalate in DNA

2. Generation of free radicals due to presence of hydroxyquinone moiety

Question 20

What is the effect of anthracycline free radical damage?

Answer 20

1. Attack DNA causing DNA cleavage

2. Lipid peroxidation

Question 21

Where is lipid peroxidation most dangerous?

Answer 21

In cardiac tissue

Basis of severe side effects of anthracycline therapy

Question 22

How do antimetabolites interfere with production of DNA and RNA?

Answer 22

1. Inhibition of normal precursor production

2. Substitution of purines and pyrimidines in normal nucleic acid synthesis

Question 23

What is administered with methotrexate to salvage normal tissues?

Answer 23

Leucovorin

Question 24

Why is leucovorin unaffected by methotrexate?

Answer 24

Does not require dihydrofolate reductase for its conversion to tetrahydrofolate

Question 25

Why does leucovorin reduce methotrexate toxicity only in normal cells

Answer 25

Allows for a small amount of pyrimidine synthesis, which is enough for normal cells but not for tumour cells, which have a much higher tetrahydrofolate requirement

Question 26

What is the role of topoisomerases?

Answer 26

Permit selected regions of DNA to become sufficiently untangled to allow replication and transcription

Question 27

What is the major component of microtubules?

Answer 27

Tubulin dimer

Protein complex containing two non-identical α and β subunits

Arranged head-to-tail in linear protofilaments

Question 28

How many tubulin protofilaments form a microtubule?

Answer 28

13

Question 29

Which end of the microtubule is usually anchored in an organising centre?

Answer 29

The minus end

Question 30

What occurs at the plus end of the microtubule?

Answer 30

Growth or shrinkage of microtubule

Question 31

How can the response of breast cancer to hormonal therapy be predicted?

Answer 31

Amounts of oestrogen and progesterone receptors in tumour tissue

Question 32

Where does tamoxifen exert oestrogen agonist effects?

Answer 32

Bone and uterus

Question 33

Which enzyme converts androgen precursors to estradiol?

Answer 33

Aromatase

Question 34

What is the purpose of aromatase inhibitors in post-menopausal women?

Answer 34

Prevent formation of oestrogen in peripheral tissues such as muscle or fat

Question 35

What is chemical castration?

Answer 35

Biochemical inhibition of testosterone production

Question 36

What increases the risk of cardiac dysfunction from trastuzumab use?

Answer 36

Coadministration with anthracyclines

Question 37

What is bevacizumab administered with to treat metastatic colorectal cancer?

Answer 37

5-fluoro-uracil

Question 38

Describe the structure of the EGFR

Answer 38

1. Transmembrane glycoprotein
2. Extra-cellular ligand-binding domain
3. Intracellular RTK domain

Question 39

How is the EGFR activated?

Answer 39

Ligand-binding causes autophosphorylation and increased biological activity

Question 40

What type of activity does the BCR-ABL protein have?

Answer 40

Tyrosine kinase activity