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Fall 2021: Therapeutics III > Alkylating Agents & Platinum Compounds (Dykhuizen) > Flashcards

Alkylating Agents & Platinum Compounds (Dykhuizen) Flashcards

1
Q

What are alkylating agents?

A

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

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2
Q

What is the most common site of alkylation?

A

guanine N7

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3
Q

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

A

bifunctional

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4
Q

What two processes does cross-linking inhibit?

A

DNA replication and transcription

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5
Q

Are akylating agents cell cycle phase specific?

A

no

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6
Q

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

A

sulfur mustard (mustard gas)

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7
Q

Alkylating agents are potent __________.

A

electrophiles

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8
Q

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

A

intrastrand = same strand

interstrand = separate strands

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9
Q

What happens if glutathione in cells reacts with alkylating agents?

A

it quenches their activity, inactivating them

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10
Q

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

A
  • thiols
  • amines
  • cysteine and lyseine residues in proteins
  • glutathione
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11
Q

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

A

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

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12
Q

What is the most notable side effect of DNA alkylation?

A

second malignancies

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13
Q

What types of DNA damage can cross-linkers cause?

A
  • preventing replication or transcription
  • mispairing
  • DNA fragmentation
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14
Q

What other names does mechlorethamine go by?

A
  • Mustargen
  • Mustine
  • Chlormethine
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15
Q

What are the side effets of mechlorethamine?

A
  • myelosuppression
  • nausea/vomiting
  • carcinogenic and teratogenic
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16
Q

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

A

by adding aryl groups

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17
Q

What three compounds are aryl mechlorethamine derivatives?

A
  • chlorambucil
  • bendamustine
  • melphalan
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18
Q

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

A

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

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19
Q

What is the prodrug mechlorethamine derivative?

A

cyclophosphamide

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20
Q

What is the activating step for cyclophosphamide?

A

hydroxylation by hepatic cytochrome P450

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21
Q

In cyclophosphamide, what metabolite cross-links DNA?

A

phosphoramide mustard (PM)

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22
Q

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

A

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

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23
Q

What inactivates cyclophosphamide’s hydroxylated metabolite?

A

aldehyde dehydrogenase

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24
Q

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

A

elevated aldehyde dehydrogenase in some bone marrow progenitor cells

25
Q

What side effects are associated with cyclophosphamide?

A
  • mild bone marrow toxicity
  • hemorrhagic cystitis (acrolein is toxic to bladder mucosa)
26
Q

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

A

ifosfamide

27
Q

What is mesna primarily used for?

A

administered with cyclophosphamide to block hemorrhagic cystitis

28
Q

How does mesna help block hemorrhagic cystitis associated with cyclophosphamide?

A

its free thiol reacts with and inactivates acrolein metabolites

29
Q

What component of mesna allows it to NOT penetrate cells?

A

a charged (anionic) sulfonate group

30
Q

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

A

false

31
Q

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

A

cyclophosphamide

32
Q

Give two examples of nitrosoureas.

A
  • bis-chloroethylnitrosourea (BCNU) (Carmustine)
  • Lomustine
33
Q

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

A

they are highly lipophilic and readily cross the BBB

34
Q

What toxicity is most prevalent with nitrosoureas?

A

bone marrow toxicity (delayed and prolonged)

35
Q

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

A

requires longer interval between doses than other agents

36
Q

Give an example of an alkyl sulfonate.

A

busulfan

37
Q

What is busulfan indicated for?

A

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

38
Q

What is the limiting toxicity of busulfan?

A

pulmonary fibrosis (“busulfan lung”)

39
Q

What type of compound is mitomycin C (Mutamycin)?

A

arizidine-containing natural product

40
Q

What is the dose-limiting toxicity of mitomycin C?

A

myelosuppression

41
Q

Give an example of a mono-alkylating agent.

A

temozolamide (or, less commonly, dacarbazine)

42
Q

TMZ utilizes which highly reactive methylating agent?

A

methyldiazonium ion

43
Q

What processes does temozolamide inhibit?

A

DNA, RNA, and protein synthesis

44
Q

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

A

true

45
Q

What toxicities are most prevalent with temozolamide?

A
  • milder bone marrow toxicity
  • severe nausea/vomiting
46
Q

What is TMZ indicated for?

A

brain cancers

47
Q

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

A

MGMT

48
Q

What process typically silences MGMT?

A

DNA methylation

49
Q

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

A

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

50
Q

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

A

cross-link (covalently)

51
Q

What geometry does cisplatin have?

A

cis geometry

52
Q

Cisplatin undergoes ________ ___________ in aqueous solution.

A

reversible hydrolysis

53
Q

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

A

cisplatin; aquo form

54
Q

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

A

guanine N7 and adenine N7

55
Q

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

A

intrastrand

56
Q

What is cisplatin indicated for?

A

many solid tumors

57
Q

What is the side effect profile for cisplatin?

A
  • dose-limiting nephrotoxicity (proximal tubule)
  • severe nausea/vomiting (centrally mediated)
  • minimal bone marrow toxicity
  • peripheral neuropathy related to cumulative dose
  • ototoxicity
58
Q

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

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

Fall 2021: Therapeutics III (25 decks)

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