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PHRM 864 Therapeutics > Alkylating Agents and Platinum Compounds Dykhuizen > Flashcards

Alkylating Agents and Platinum Compounds Dykhuizen Flashcards

1
Q

What rescues a 5-FU overdose? (review)

A. Leucovorin
B. Cytosine arabinoside
C. Thymidine
D. Methotrexate

A

C. Thymidine

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2
Q

Which antimetabolite should NOT be given to patients being treated for gout? (review)

A. Cytosine Arabinoside
B. 6-mercaptopurine
C. Cladribine
D. 5-FU

A

B. 6-mercaptopurine

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2
Q

What increases the efficacy of 5-FU? (review)

A. Leucovorin
B. Cytosine arabinoside
C. Thymidine
D. Methotrexate

A

A. Leucovorin

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3
Q

Which anti-metabolite does NOT directly inhibit DNA/RNA synthesis? (review)

A. 5-fluorouracil
B. Cytosine Arabinoside
C. Nelarabine
D. Methotrexate

A

D. Methotrexate

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4
Q

alkylating agents generate reactive _______ intermediates that react with _______ groups on DNA and proteins

a. electrophilic; electrophilic
b. electrophilic; nucleophilic
c. nucleophilic; nucleophilic
d. nucleophilic; electrophilic

A

b. electrophilic; nucleophilic

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5
Q

most common site of alkylation

A

guanine N7

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6
Q

T or F: alkylating agents are cell-cycle phase specific

A

F

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7
Q

T or F: most effective anti-cancer drugs are bifunctional alkylating agents that produce DNA intra- and interstrand linkages

A

T

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8
Q

the MOA of alkylating agents involves alkylation of ______ bases in DNA

a. purine
b. pyrimidine

A

a. purine (A and G)

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9
Q

Alkylating agents are potent…

A. Reducing agents
B. Electrophiles
C. Nucleophiles
D. Oxidizing agents

A

B. Electrophiles

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10
Q

which two phases of the cell cycle are cancer cells more susceptible to alkylation?

A

G1 and S

(but alkylating agents are still non cell-cycle specific)

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11
Q

T or F: there is a measurable incidence of second malignancies in long-term survivors following chemo with alkylating agents

A

T

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12
Q

most second malignancies following chemo with alkylating agents usually occurs where?

A

bone marrow (leukemia)

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13
Q

alkylating agents that act nonspecifically cause what types of DNA damage? (SELECT ALL THAT APPLY)

a. cross-bridges
b. mispairing
c. DNA fragmentation

A

a. cross-bridges

(this prevents replication or transcription)

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14
Q

alkylating agents that act specifically cause what types of DNA damage? (SELECT ALL THAT APPLY)

a. prevent replication or transcription
b. mispairing
c. DNA fragmentation

A

b. mispairing
c. DNA fragmentation

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15
Q

plasma half-life of mechlorethamine

a. 30 sec
b. 1 min
c. 5 min
d. 5 days

A

b. 1 min

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16
Q

SE of all alkylators (4 of them)

A

-myelosuppression
-N/V
-carcinogenic
-teratogenic

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17
Q

two strategies to reduce reactivity and inc selectivity of nitrogen mustards

A
  1. dec nucleophilicity of nitrogen by adding aryl groups
  2. prodrug
18
Q

how do aromatic rings reduce nucleophilicity for mechlorethamine derivatives?

A

we want to reduce the electron density around the N, by putting an aromatic ring, it pulls electron density away; stronger acid = weaker conjugate base, resonance stabilized

19
Q

the aziridinium intermediate for mustards are the __________ group

a. nucleophilic
b. electrophilic

A

b. electrophilic

20
Q

T or F: cyclophosphamide is a prodrug

A

T

21
Q

T or F: mechlorethamine requires hydroxylation by hepatic cytochrome P450

A

F (cyclophosphamide)

22
Q

what is the metabolite of cyclophosphamide that cross-links DNA?

a. acrolein
b. ifosfamide
c. bendamustine
d. phosphoramide mustard
e. aziridinium

A

d. phosphoramide mustard (PM)

23
Q

phosphoramide mustard (PM) is inactivated by which enzyme?

A

aldehyde dehydrogenase

24
Q

what byproduct of cyclophosphamide is toxic to bladder mucosa and causes hemorrhagic cystitis?

a. PM
b. acrolein
c. aziridinium
d. Mesna

A

b. acrolein

25
Q

what is the most useful and commonly used alkylating agent?

A

cyclophosphamide

26
Q

two SE bolded for cyclophosphamide (slide 23)

A

mild bone marrow toxicity
hemorrhagic cystitis

27
Q

________ has a longer half life than cyclophosphamide, but also has inc CNS toxicity

A

ifosfamide

28
Q

what drug is given with cyclophosphamide to block hemorrhagic cystitis?

a. ifosfamide
b. Mitomycin C
c. Mesna
d. 6-mercaptopurine

A

c. Mesna

29
Q

dose-limiting SE of mitomycin C

A

myelosuppression

30
Q

T or F: mitomycin C can form bifunctional adducts (crosslinks)

A

T

31
Q

Which of the following is a prodrug?

A. Mechlorethamine
B. Cyclophosphamide
C. Mitomycin C
D. Chlorambucil

A

B. Cyclophosphamide

32
Q

T or F: platinum drugs cannot form covalent crosslinks

A

F (they do, but they are not alkylating agents)

33
Q

original prototype platinum drug

A

cisplatin

34
Q

leaving groups in cisplatin have ____ geometry

a. cis
b. trans

A

a. cis

35
Q

what form of cisplatin is highly reactive and a potent electrophile?

A

the aquo form

36
Q

platinum crosslink geometry:

-Aquo form reacts primarily at _______ N-7 and _______ N-7 in DNA
-Because of bond lengths and angles, cross-links are often _______

A

Guanine; Adenine; intrastrand

37
Q

what is the basic difference in the MOA of alkylating agents and platinum compounds?

A

they form a diff type of crosslink

38
Q

which of the following is TRUE about cisplatin?

a. cisplatin is not effective for solid tumors
b. drug requires non-enzymatic conversion to the active aquo form
c. aquo form primarily produces interstrand cross-links
d. some tumor cells more sensitive in S phase than G1
e. cross-links generally form faster than for other alkylating agents

A

b. drug requires non-enzymatic conversion to the active aquo form

(C is intrastrand; D is more sensitive in G1; E is slower)

39
Q

which is FALSE about cisplatin side effects?

a. dose-limiting nephrotoxicity (proximal tubule)
b. severe N/V (centrally mediated)
c. high bone marrow toxicity
d. peripheral neuropathy
e. ototoxicity (hearing loss)

A

c. high bone marrow toxicity (minimal)

40
Q

which of the following is not a drug resistance mechanism for alkylating agents and platinum drugs? (slide 32)

a. Dec expression of DNA repair enzymes
b. Inc intracellular conc of non-protein thiols, especially glutathione
c. Inc expression of cellular glutathione S-transferase (GST)

A

a. Dec expression of DNA repair enzymes

41
Q

T or F: free thiols have very low reactivity toward electrophilic intermediates

A

F (extremely high)

42
Q
A

PHRM 864 Therapeutics (28 decks)

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