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PHRM 864 > L alkylating and platinum > Flashcards

L alkylating and platinum Flashcards

1
Q

alkylating agents are drugs that generate reactive ________ intermediates that react with ________ groups on DNA and proteins

A

electrophilic
nucleophilic

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2
Q

the major MOA involves alkylation of ______ bases in DNA

A

purine

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3
Q

what is the most common site of alkylation (answer has a nucelotide and something random)

A

guanine n7 (i later figured out that it is the nitrogen on the 7 position, im dumb)

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4
Q

most effective anti-cancer drugs are ________ alkylating agents that produce DNA intra- and inter-strand linkages (whatever tf this means)

A

bifunctional, guess that makes sense with 2 things there huh

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5
Q

Cross-links (caused by the alkylating groups that produce intra and inter strand dna linkages) inhibit what and what?

A

DNA replication
DNA transcription

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6
Q

T or F:
alkylating agents are cell-phase specifc

A

false, they are not

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7
Q

what common condiment is also a type of gas that can alkylate?

A

mustard lmao

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8
Q

Alkylating agents are potent…

A. Reducing agents

B. Electrophiles

C. Nucleophiles

D. Oxidizing agents

A

B

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9
Q

linking between two bases on the same strand
A. inTRAstrand
B. inTERstrand

A

A. inTRastrand

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10
Q

cross-linking of two separate strands
A. inTRAstand
B. inTERstrand

A

B. inTERstrand

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11
Q

what other nucleophilic-things can alkylating agents react with that aren’t DNA bases?

A

Thiols * (main one i think bc of sulfur)
amines
cysteine and lysine residues
glutathione

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12
Q

T or F:
Toxicity to cancer cells results from DNA alkylation and DNA cross-linking

A

True

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13
Q

T or F:
DNA-protein cross links also inhibit DNA function

A

true

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14
Q

Cells are more susceptible to alkylating agents in what 2 phases of the cell cycle?

A

G1 and S

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15
Q

what are the two locations in body that are most sensitive to DNA alkylation and cross-linking (important for side effects)?

A

bone marrow
gut mucosa

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16
Q

T or F:
Mono-adducts are mutagenic but not carcinogenic

A

False, it is both mutagenic and carcinogenic

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17
Q

There are a measurable incidence of 2nd malignancies in long-term survivors following chemo w/ alkylating agents, where do these malignancies arise?

A

bone marrow as leukemias

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18
Q

3 side effects for all alkylators *

A

myelosuppression
N/V
carcinogenic and teratogenic

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19
Q

Chlorambucil is a __________ derivative that decreases __________ of nitrogen by adding aryl groups

A

mechlorethamine
nucleophilicity

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20
Q

what are the 2 strategies to reduce reactivity and increase the selectivity of nitrogen mustards (mainly just making mechlorethamine better)?

A
  • decrease nucleophilicity of nitrogen by adding aryl groups
  • prodrug strategy with cyclophosphamide that helps the mustard compounds get into cells
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21
Q

what is another way of saying you added an aryl group

A

you added an aromatic ring

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22
Q

Cyclophosphamide is a chemically stable ______

A

prodrug

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23
Q

since cyclophosphamide is a prodrug, what does it require to be activated?

A

hydroxylation by CP450

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24
Q

Phosphoramide mustard (PM) is the metabolite that _________ DNA
A. Creates an interstrand linkage with
B. Creates an intrastrand linkage with
C. Cross-links

A

C

25
Q

the hydroxylated metabolite from cyclophosphamide must be converted to PM, where does this happen?

A

in the tumor cell

think that its a prodrug and has to have help getting into the cancer cells

26
Q

quick! you see the word “acrolein” on the exam, what do you start thinking about instantly because you studied hard?

A

Cyclophosphamide and aldehyde dehydrogenase

27
Q

what is an enzyme that can deactivate the metabolite derived from cyclophosphamide?

A

aldehyde dehydrogenase

28
Q

T or F: Aldehyde dehydrogenase inactivating the cyclophosphamide metabolites is bad

A

false, its actually good because we have higher levels of aldehyde dehydrogenase in our bone marrow and that means you reduce the activity there which leads to a reduction in myelosuppression (wordy af im sorry)

29
Q

Most commonly used and useful alkylating agent

A

cyclophosphamide

30
Q

2 side effects from cyclophosphamide slide**

A

-mild bone marrow toxicity
-hemorrhagic cystitis (from acrolein metabolite)

31
Q

what is the drug in the same class as cyclophosphamide that has a longer half life with increased CNS toxicity?

A

Ifosfamide

32
Q

Cyclophosphamide is toxic to the _____ (organ). Why?

A

bladder, acrolein accumulates in urine and damages bladder mucosa

33
Q

T or F:
Mesna penetrates cells

A

false, it cant because it has a charged sulfonate group

34
Q

Mesna accumulates in _______**

A

urine

35
Q

The free thiol on mesna reacts with and inactivates _____ metabolites in urine

A

acrolein

36
Q

Why is mesna administered with cyclophosphamide? **

A

To block hemorrhagic cystitis

37
Q

Mitomycin C functions as what?

A

an alkylating agent

38
Q

mitomycin C has a different toxicity pattern than other alkylating agents, what is the main difference with it? (not the reason behind the difference)

A

myelosuppression is dose-limiting

39
Q

Platinum drugs are _____ crosslinkers, but not ________ ________

A

covalent
alkylating agents

40
Q

what drug is the OG prototype of platinum drugs

A

cisplatin (goated)

41
Q

cisplatin is a square planar complex with leaving groups having ____ geometry

A

cis, no fuckin way.

42
Q

T or F:
Cisplatin undergoes irreversible hydrolysis in aqueous solution

A

false, it is reversible

43
Q

T or F:
Equilibrium favors cisplatin in plasma

A

True, it’s in the name bro come on

44
Q

Equilibrium favors aquo from (inside/outside) cell

A

inside

45
Q

aquo form is highly reactive and a potent _________

A

electrophile

46
Q

Cisplatin is given with what element as its leaving groups/

A

chlorine

47
Q

What replaces the Cl- leaving groups on cisplatin once it is in the cell?

A

water (h2o)

48
Q

Platinum crosslink geometry:
Because of bond lengths and angles, cross-links are often ___________*

A

intrastrand

49
Q

T or F:
Aldehyde dehydrogenase converts cisplatin to the active aquo form

A

False, it is a non-enzymatic conversion

50
Q

Cisplatin is a highly effective agent for many ____ tumors

A

solid

51
Q

Cross-links formed with cisplatin are generally (faster/slower) than for other alkylating agents

A

slower

52
Q

Cisplatin:
Some tumor cells are more sensitive in __ phase than S phase

A

G1

53
Q

2 highlighted side effects on cisplatin slide (notably very different than other agents)

A
  • dose limiting nephrotoxicity
  • minimal bone marrow toxicity
54
Q

Drug resistance - general mechanisms:
Increased expression of DNA ______ enzymes

A

repair

55
Q

Drug resistance - general mechanisms:
Increased intracellular concentration of non-protein thiols especially ______ **

A

glutathione

56
Q

Free thiols have extremely (low/high) reactivity toward electrophilic intermediates *

A

high

57
Q

Drug resistance - general mechanisms:
increased expression of cellular _________________ *

A

glutathione S-transferase (GST)

58
Q

glutathione s-transferase (GST) catalyzes the reaction of ________ with __________ __________

A

glutathione
alkylating agents

PHRM 864 (28 decks)

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