Alkylating Agents & Platinum Compounds (Dykhuizen)

Question 1

What are alkylating agents?

Answer 1

drugs that generate reactive electrophilic intermediates that react with nucleophilic groups on DNA and proteins, resulting in the attachment of an aryl group

Question 2

What is the most common site of alkylation?

Answer 2

guanine N7

Question 3

The most effective anti-cancer drugs are ________ alkylating agents.

Answer 3

bifunctional

Question 4

What two processes does cross-linking inhibit?

Answer 4

DNA replication and transcription

Question 5

Are akylating agents cell cycle phase specific?

Answer 5

no

Question 6

What compound was used by doctors in the 1940s to treat leukemia and lymphoma?

Answer 6

sulfur mustard (mustard gas)

Question 7

Alkylating agents are potent __________.

Answer 7

electrophiles

Question 8

What is the difference between intrastrand and interstrand cross-linking?

Answer 8

intrastrand = same strand

interstrand = separate strands

Question 9

What happens if glutathione in cells reacts with alkylating agents?

Answer 9

it quenches their activity, inactivating them

Question 10

Besides DNA bases, what else do alkylating agents react with?

Answer 10

• thiols
• amines
• cysteine and lyseine residues in proteins
• glutathione

Question 11

When in the cycle are cells more susceptible to DNA alkylation?

Answer 11

late G₁ and S phases (although still considered to be non-specific)

Question 12

What is the most notable side effect of DNA alkylation?

Answer 12

second malignancies

Question 13

What types of DNA damage can cross-linkers cause?

Answer 13

• preventing replication or transcription
• mispairing
• DNA fragmentation

Question 14

What other names does mechlorethamine go by?

Answer 14

• Mustargen
• Mustine
• Chlormethine

Question 15

What are the side effets of mechlorethamine?

Answer 15

• myelosuppression
• nausea/vomiting
• carcinogenic and teratogenic

Question 16

In order to reduce reactivity and increase selectivity of nitrogen mustards, one method is to decrease the nucleophilicity of nitrogen. How is this done?

Answer 16

by adding aryl groups

Question 17

What three compounds are aryl mechlorethamine derivatives?

Answer 17

• chlorambucil
• bendamustine
• melphalan

Question 18

How does adding an aromatic ring to nitrogen mustards reduce nucleophilicity?

Answer 18

it pulls electron density away from the nitrogen, ultimately making it less reactive

Question 19

What is the prodrug mechlorethamine derivative?

Answer 19

cyclophosphamide

Question 20

What is the activating step for cyclophosphamide?

Answer 20

hydroxylation by hepatic cytochrome P450

Question 21

In cyclophosphamide, what metabolite cross-links DNA?

Answer 21

phosphoramide mustard (PM)

Question 22

True or false: cyclophosphamide’s hydroxylated metabolite can be converted to PM outside of the tumor cell.

Answer 22

false; it is highly polar and does not readily diffuse into cells, so it must be converted inside the tumor

Question 23

What inactivates cyclophosphamide’s hydroxylated metabolite?

Answer 23

aldehyde dehydrogenase

Question 24

What accounts for reduced bone marrow toxicity in cyclophosphamide compared to other agents?

Answer 24

elevated aldehyde dehydrogenase in some bone marrow progenitor cells

Question 25

What side effects are associated with cyclophosphamide?

Answer 25

* mild bone marrow toxicity * hemorrhagic cystitis (acrolein is toxic to bladder mucosa)

Question 26

Which drug is known to have a longer half-life than cyclophosphamide, but also has increased CNS toxicity?

Answer 26

ifosfamide

Question 27

What is mesna primarily used for?

Answer 27

administered with cyclophosphamide to block hemorrhagic cystitis

Question 28

How does mesna help block hemorrhagic cystitis associated with cyclophosphamide?

Answer 28

its free thiol reacts with and inactivates acrolein metabolites

Question 29

What component of mesna allows it to NOT penetrate cells?

Answer 29

a charged (anionic) sulfonate group

Question 30

True or false: mesna does not accumulate in the urine.

Answer 30

false

Question 31

Which of the following is a prodrug: mechlorethamine, cyclophosphamide, mesna, or chlorambucil?

Answer 31

cyclophosphamide

Question 32

Give two examples of nitrosoureas.

Answer 32

* bis-chloroethylnitrosourea (BCNU) (Carmustine) * Lomustine

Question 33

What characteristic of nitrosoureas makes them indicated for glioblastoma multiforme and other brain tumors?

Answer 33

they are highly lipophilic and readily cross the BBB

Question 34

What toxicity is most prevalent with nitrosoureas?

Answer 34

bone marrow toxicity (delayed and prolonged)

Question 35

What dosing decision should be made when thinking about nitrosoureas' delayed and prolonged myelosuppression?

Answer 35

requires longer interval between doses than other agents

Question 36

Give an example of an alkyl sulfonate.

Answer 36

busulfan

Question 37

What is busulfan indicated for?

Answer 37

given in high doses with cyclophosphamide before a bone marrow transplant to eradicate all hematopoeitic cells

Question 38

What is the limiting toxicity of busulfan?

Answer 38

pulmonary fibrosis ("busulfan lung")

Question 39

What type of compound is mitomycin C (*Mutamycin*)?

Answer 39

arizidine-containing natural product

Question 40

What is the dose-limiting toxicity of mitomycin C?

Answer 40

myelosuppression

Question 41

Give an example of a mono-alkylating agent.

Answer 41

temozolamide (or, less commonly, dacarbazine)

Question 42

TMZ utilizes which highly reactive methylating agent?

Answer 42

methyldiazonium ion

Question 43

What processes does temozolamide inhibit?

Answer 43

DNA, RNA, and protein synthesis

Question 44

True or false: TMZ can be combined with other alkylating agents.

Answer 44

true

Question 45

What toxicities are most prevalent with temozolamide?

Answer 45

* milder bone marrow toxicity * severe nausea/vomiting

Question 46

What is TMZ indicated for?

Answer 46

brain cancers

Question 47

What compound can make TMZ less effective and lead to resistance?

Answer 47

MGMT

Question 48

What process typically silences MGMT?

Answer 48

DNA methylation

Question 49

How can we predict whether glioblastoma patients will respond to TMZ?

Answer 49

looking at promoter methylation...if unmethylated, there is no point in giving TMZ

Question 50

Do platinum drugs cross-link, alylate, or both?

Answer 50

cross-link (covalently)

Question 51

What geometry does cisplatin have?

Answer 51

cis geometry

Question 52

Cisplatin undergoes ________ \_\_\_\_\_\_\_\_\_\_\_ in aqueous solution.

Answer 52

reversible hydrolysis

Question 53

Equilibrium favors ________ in plasma, and ________ inside the cell.

Answer 53

cisplatin; aquo form

Question 54

The aquo form of cisplatin reacts primarily at which two DNA sites?

Answer 54

guanine N7 and adenine N7

Question 55

Because of bond lengths and angles, cisplatin cross-links are often \_\_\_\_\_\_\_\_\_.

Answer 55

intrastrand

Question 56

What is cisplatin indicated for?

Answer 56

many solid tumors

Question 57

What is the side effect profile for cisplatin?

Answer 57

* dose-limiting nephrotoxicity (proximal tubule) * severe nausea/vomiting (centrally mediated) * minimal bone marrow toxicity * peripheral neuropathy related to cumulative dose * ototoxicity

Question 58

What are the three general mechanisms for alkylating and platinum drug resistance?

Answer 58

1. increased expression of DNA repair enzymes 2. increased intracellular concentration of non-protein thiols (esp. glutathione) 3. increased expression of GST