Alkylating Agents and Platinum Compounds Dykhuizen Flashcards
What rescues a 5-FU overdose? (review)
A. Leucovorin
B. Cytosine arabinoside
C. Thymidine
D. Methotrexate
C. Thymidine
Which antimetabolite should NOT be given to patients being treated for gout? (review)
A. Cytosine Arabinoside
B. 6-mercaptopurine
C. Cladribine
D. 5-FU
B. 6-mercaptopurine
What increases the efficacy of 5-FU? (review)
A. Leucovorin
B. Cytosine arabinoside
C. Thymidine
D. Methotrexate
A. Leucovorin
Which anti-metabolite does NOT directly inhibit DNA/RNA synthesis? (review)
A. 5-fluorouracil
B. Cytosine Arabinoside
C. Nelarabine
D. Methotrexate
D. Methotrexate
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
b. electrophilic; nucleophilic
most common site of alkylation
guanine N7
T or F: alkylating agents are cell-cycle phase specific
F
T or F: most effective anti-cancer drugs are bifunctional alkylating agents that produce DNA intra- and interstrand linkages
T
the MOA of alkylating agents involves alkylation of ______ bases in DNA
a. purine
b. pyrimidine
a. purine (A and G)
Alkylating agents are potent…
A. Reducing agents
B. Electrophiles
C. Nucleophiles
D. Oxidizing agents
B. Electrophiles
which two phases of the cell cycle are cancer cells more susceptible to alkylation?
G1 and S
(but alkylating agents are still non cell-cycle specific)
T or F: there is a measurable incidence of second malignancies in long-term survivors following chemo with alkylating agents
T
most second malignancies following chemo with alkylating agents usually occurs where?
bone marrow (leukemia)
alkylating agents that act nonspecifically cause what types of DNA damage? (SELECT ALL THAT APPLY)
a. cross-bridges
b. mispairing
c. DNA fragmentation
a. cross-bridges
(this prevents replication or transcription)
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
b. mispairing
c. DNA fragmentation
plasma half-life of mechlorethamine
a. 30 sec
b. 1 min
c. 5 min
d. 5 days
b. 1 min
SE of all alkylators (4 of them)
-myelosuppression
-N/V
-carcinogenic
-teratogenic
two strategies to reduce reactivity and inc selectivity of nitrogen mustards
- dec nucleophilicity of nitrogen by adding aryl groups
- prodrug
how do aromatic rings reduce nucleophilicity for mechlorethamine derivatives?
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
the aziridinium intermediate for mustards are the __________ group
a. nucleophilic
b. electrophilic
b. electrophilic
T or F: cyclophosphamide is a prodrug
T
T or F: mechlorethamine requires hydroxylation by hepatic cytochrome P450
F (cyclophosphamide)
what is the metabolite of cyclophosphamide that cross-links DNA?
a. acrolein
b. ifosfamide
c. bendamustine
d. phosphoramide mustard
e. aziridinium
d. phosphoramide mustard (PM)
phosphoramide mustard (PM) is inactivated by which enzyme?
aldehyde dehydrogenase
what byproduct of cyclophosphamide is toxic to bladder mucosa and causes hemorrhagic cystitis?
a. PM
b. acrolein
c. aziridinium
d. Mesna
b. acrolein
what is the most useful and commonly used alkylating agent?
cyclophosphamide
two SE bolded for cyclophosphamide (slide 23)
mild bone marrow toxicity
hemorrhagic cystitis
________ has a longer half life than cyclophosphamide, but also has inc CNS toxicity
ifosfamide
what drug is given with cyclophosphamide to block hemorrhagic cystitis?
a. ifosfamide
b. Mitomycin C
c. Mesna
d. 6-mercaptopurine
c. Mesna
dose-limiting SE of mitomycin C
myelosuppression
T or F: mitomycin C can form bifunctional adducts (crosslinks)
T
Which of the following is a prodrug?
A. Mechlorethamine
B. Cyclophosphamide
C. Mitomycin C
D. Chlorambucil
B. Cyclophosphamide
T or F: platinum drugs cannot form covalent crosslinks
F (they do, but they are not alkylating agents)
original prototype platinum drug
cisplatin
leaving groups in cisplatin have ____ geometry
a. cis
b. trans
a. cis
what form of cisplatin is highly reactive and a potent electrophile?
the aquo form
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 _______
Guanine; Adenine; intrastrand
what is the basic difference in the MOA of alkylating agents and platinum compounds?
they form a diff type of crosslink
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
b. drug requires non-enzymatic conversion to the active aquo form
(C is intrastrand; D is more sensitive in G1; E is slower)
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)
c. high bone marrow toxicity (minimal)
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. Dec expression of DNA repair enzymes
T or F: free thiols have very low reactivity toward electrophilic intermediates
F (extremely high)
