L alkylating and platinum Flashcards
alkylating agents are drugs that generate reactive ________ intermediates that react with ________ groups on DNA and proteins
electrophilic
nucleophilic
the major MOA involves alkylation of ______ bases in DNA
purine
what is the most common site of alkylation (answer has a nucelotide and something random)
guanine n7 (i later figured out that it is the nitrogen on the 7 position, im dumb)
most effective anti-cancer drugs are ________ alkylating agents that produce DNA intra- and inter-strand linkages (whatever tf this means)
bifunctional, guess that makes sense with 2 things there huh
Cross-links (caused by the alkylating groups that produce intra and inter strand dna linkages) inhibit what and what?
DNA replication
DNA transcription
T or F:
alkylating agents are cell-phase specifc
false, they are not
what common condiment is also a type of gas that can alkylate?
mustard lmao
Alkylating agents are potent…
A. Reducing agents
B. Electrophiles
C. Nucleophiles
D. Oxidizing agents
B
linking between two bases on the same strand
A. inTRAstrand
B. inTERstrand
A. inTRastrand
cross-linking of two separate strands
A. inTRAstand
B. inTERstrand
B. inTERstrand
what other nucleophilic-things can alkylating agents react with that aren’t DNA bases?
Thiols * (main one i think bc of sulfur)
amines
cysteine and lysine residues
glutathione
T or F:
Toxicity to cancer cells results from DNA alkylation and DNA cross-linking
True
T or F:
DNA-protein cross links also inhibit DNA function
true
Cells are more susceptible to alkylating agents in what 2 phases of the cell cycle?
G1 and S
what are the two locations in body that are most sensitive to DNA alkylation and cross-linking (important for side effects)?
bone marrow
gut mucosa
T or F:
Mono-adducts are mutagenic but not carcinogenic
False, it is both mutagenic and carcinogenic
There are a measurable incidence of 2nd malignancies in long-term survivors following chemo w/ alkylating agents, where do these malignancies arise?
bone marrow as leukemias
3 side effects for all alkylators *
myelosuppression
N/V
carcinogenic and teratogenic
Chlorambucil is a __________ derivative that decreases __________ of nitrogen by adding aryl groups
mechlorethamine
nucleophilicity
what are the 2 strategies to reduce reactivity and increase the selectivity of nitrogen mustards (mainly just making mechlorethamine better)?
- decrease nucleophilicity of nitrogen by adding aryl groups
- prodrug strategy with cyclophosphamide that helps the mustard compounds get into cells
what is another way of saying you added an aryl group
you added an aromatic ring
Cyclophosphamide is a chemically stable ______
prodrug
since cyclophosphamide is a prodrug, what does it require to be activated?
hydroxylation by CP450
Phosphoramide mustard (PM) is the metabolite that _________ DNA
A. Creates an interstrand linkage with
B. Creates an intrastrand linkage with
C. Cross-links
C
the hydroxylated metabolite from cyclophosphamide must be converted to PM, where does this happen?
in the tumor cell
think that its a prodrug and has to have help getting into the cancer cells
quick! you see the word “acrolein” on the exam, what do you start thinking about instantly because you studied hard?
Cyclophosphamide and aldehyde dehydrogenase
what is an enzyme that can deactivate the metabolite derived from cyclophosphamide?
aldehyde dehydrogenase
T or F: Aldehyde dehydrogenase inactivating the cyclophosphamide metabolites is bad
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)
Most commonly used and useful alkylating agent
cyclophosphamide
2 side effects from cyclophosphamide slide**
-mild bone marrow toxicity
-hemorrhagic cystitis (from acrolein metabolite)
what is the drug in the same class as cyclophosphamide that has a longer half life with increased CNS toxicity?
Ifosfamide
Cyclophosphamide is toxic to the _____ (organ). Why?
bladder, acrolein accumulates in urine and damages bladder mucosa
T or F:
Mesna penetrates cells
false, it cant because it has a charged sulfonate group
Mesna accumulates in _______**
urine
The free thiol on mesna reacts with and inactivates _____ metabolites in urine
acrolein
Why is mesna administered with cyclophosphamide? **
To block hemorrhagic cystitis
Mitomycin C functions as what?
an alkylating agent
mitomycin C has a different toxicity pattern than other alkylating agents, what is the main difference with it? (not the reason behind the difference)
myelosuppression is dose-limiting
Platinum drugs are _____ crosslinkers, but not ________ ________
covalent
alkylating agents
what drug is the OG prototype of platinum drugs
cisplatin (goated)
cisplatin is a square planar complex with leaving groups having ____ geometry
cis, no fuckin way.
T or F:
Cisplatin undergoes irreversible hydrolysis in aqueous solution
false, it is reversible
T or F:
Equilibrium favors cisplatin in plasma
True, it’s in the name bro come on
Equilibrium favors aquo from (inside/outside) cell
inside
aquo form is highly reactive and a potent _________
electrophile
Cisplatin is given with what element as its leaving groups/
chlorine
What replaces the Cl- leaving groups on cisplatin once it is in the cell?
water (h2o)
Platinum crosslink geometry:
Because of bond lengths and angles, cross-links are often ___________*
intrastrand
T or F:
Aldehyde dehydrogenase converts cisplatin to the active aquo form
False, it is a non-enzymatic conversion
Cisplatin is a highly effective agent for many ____ tumors
solid
Cross-links formed with cisplatin are generally (faster/slower) than for other alkylating agents
slower
Cisplatin:
Some tumor cells are more sensitive in __ phase than S phase
G1
2 highlighted side effects on cisplatin slide (notably very different than other agents)
- dose limiting nephrotoxicity
- minimal bone marrow toxicity
Drug resistance - general mechanisms:
Increased expression of DNA ______ enzymes
repair
Drug resistance - general mechanisms:
Increased intracellular concentration of non-protein thiols especially ______ **
glutathione
Free thiols have extremely (low/high) reactivity toward electrophilic intermediates *
high
Drug resistance - general mechanisms:
increased expression of cellular _________________ *
glutathione S-transferase (GST)
glutathione s-transferase (GST) catalyzes the reaction of ________ with __________ __________
glutathione
alkylating agents
