alkylators & platinum Flashcards
Alkylators & intercalators inhibit what phase of cell cycle
All of them
Alkylating agents are drugs that generate reactive __neutrophilic/electrophilic__ intermediates that react with __electrophilic/nucleophilic__ groups on DNA and proteins.
Result in the attachment of an _____(hydrocarbon) group to DNA and protein.
Major mechanism of action involves alkylation of __purine/pyrimidine__ bases in __DNA/RNA__
> _______ is the most common site of alkylation
Most effective anti-cancer drugs are bifunctional alkylating agents (two alkylating groups) that produce DNA intra- and interstrand linkages
_______-links inhibit DNA replication, as well as transcription
Repair of cross-links in cancer cells is not efficient
Attempted replication of modified DNA can result in cell death (apoptosis)
electrophilic; neutrophilic; alkyl
purine; DNA
Guanine N7
Cross
t/f alkylators are NOT cell-cycle phase specific
true
doctors first used mustards to tx ______ and ______ in the 1940s
leukemia & lymphoma (myelosuppression)
_______ mustards (Chlormethamine, Mechlorethamine, Mustine R=CH3):
Are similar, but are _____, not gas.
They were the first chemotherapy in 1942.
Very reactive and excessively toxic
Nitrogen; liquid
All of the ring __nitrogens/carbons______have some reactivity, as well as the exocyclic oxygens.
The __electrophilicity/nucleophilicity__ is controlled by steric, electronic and ________bonding effects.
nitrogens; neutrophilicity; hydrogen bonds
Alkylating agents are potent…
A. Reducing agents
B. Electrophiles
C. Nucleophiles
D. Oxidizing agents
B. Electrophiles
match with correct definition:
intrastrand or interstrand
- linking between two bases on the same strand
- cross-linking of two separate strands
IntRAstrand linking between two bases on the same strand
intERstrand cross-linking of two separate strands
_________ agents react with many nucleophiles other than DNA bases. Thiols especially reactive, amines also reactive
also _______ and _________ residues in proteins
alkylating
thiols & amines
___________ in cells can react with alkylating agents and ”quench” their activity.
glutathione
cells are more susceptible in late ___ and ___ phases of the cell cycle but alkylating agents are considered _______ specific
G1 & S; non cell cycle
what normal cell populations are more sensitive to effects of DNA alkylation & cross-linking because they are naturally rapidly proliferation?
bone marrow & gut mucosa
_________ are a side effect of alkylation and are mutagenic and carcinogenic
> Measurable incidence of second malignancies in long-term survivors following chemotherapy with alkylating agents
Most __first/second__ malignancies arise in the bone marrow (leukemias)
Monoadducts
second –> myelosuppression (hair loss, N/V)
what drug was an important prototype that resulted in the development of field of chemotherapy, but is not used commonly anymore?
mechlorethamine (mustargen, mustine, chlormethine)
> extremely reactive compound
what are 3 side effects for all alkylators?
myelosuppression
N/V
carcinogenic & teratogenic
why should someone who is pregnant that is wanting to preserve the pregnancy not use alkylators
teratogenic
For mechlorethamine (mustards) derivatives:
what 2 strategies have been employed to reduce reactivity & increase selectivity of nitrogen mustards? give a drug example of each strategy
- decrease nucleophilicity of nitrogen by adding aryl groups (chlorambucil)
- prodrug strategy –> requires hydroxylation by hepatic cytochrome P450 (cyclophosphamide)
what are the 2 main mechlorethamine derivative that we need to know?
chlorambucil & cyclophosphamide
cyclophosphamide is a stable prodrug (mechlorethamine) that requires hydroxylation by hepatic _________.
what is the metabolite that cross-links DNA?
what metabolite inactivates the metabolite that cross-links?
cytochrome P450
phosphoramide mustard (hydroxylated metabolite must be converted to PM in tumor cell)
aldehyde dehydrogenase
what is the byproduct that is produced by cyclophosphamide?
what part of the body is this toxic to?
What needs to be administered with cyclophosphamide to prevent accumulation?
acrolein
bladder –> damages bladder mucosa
Mesna –> contained anionic sulfonate group does not penetrate cells & accumulates in urine. the free thiol on mesna reacts with acrolein and inactivates it
if mesna is not administered with cyclophosphamide what can tx lead to?
hemorrhagic cystitis
what is the most useful & commonly used alkylating agent?
cyclophosphamide
Which of the following is a prodrug?
- Mechlorethamine
- Cyclophosphamide
- Mitomycin C
- Chlorambucil
- Cyclophosphamide
what are the 2 unique sxs associated with cyclophosphamide
-mild bone marrox toxicity (high ADH levels in these cells)
-hemorrhagic cystitis (byproduct, acrolein is toxic to bladder mucosa)
mitomycin C is a ______-containing natural product
aziridine
what is the dose-limiting side effect of mitomycin c
myelosuppression
what kind of crosslinks does mitomycin C form to disrupt DNA?
bifunctional adducts
t/f platinum drugs are considered alkylating agents
FALSE; covalent crosslinkers –> they do not contain alkyl groups
___drug_______ is the orig. prototype square planar complex with leaving groups having __cis/trans___
cisPLATin; cis
Cisplatin undergoes __irreversible/reversible___ hydrolysis in aqueous solution
Equilibrium favors Cisplatin in ______ (where there is a __high/low__ chloride concentration)
Equilibrium favors aquo form __inside/outside___cell (__high/low___ chloride concentration)
__cisplatin/aquo form___ is highly reactive and a potent __neutrophile/electrophile___
therefore, it reacts rapidly with other __neutrophiles/electrophiles__ especially thiols (glutathione)
reversible
plasma; high
inside; low
aquo form; electrophile
nucleophiles
The aquo form of cisplatin reacts primarily with _________ and _________ in DNA. The reaction results in cross-links that are often __interstrand/intrastrand__
Guanine N-7 and Adenine N-7
INTRAstrand –> crosslinks induce sharp bends & lesions are not readily repaired by standard DNA repair enzymes
cisplatin is highly effective for many ______ tumors. some tumor cells are more senstive in G1 than S phase, so cisplatin is often combined w drugs that target ___ or ___ phase
solid
S or G2
what is a dose-limiting side effect of cisplatin?
what are some other unique sxs?
nephrotoxicity
-severe N/V
-minimal bone marrow toxcity (myelosuppresion)
-peripheral neuropathy
-ototoxicity
what is the most prescribed chemotherapy?
cisplatin
drug resistance of alkylating/platinum agents:
___increased/decreased___ expression of DNA repair enzymes
___increased/decreased___ intracellular concentration of non-protein thiols, especially __________
> ________ is a cysteine-containing tripeptide (gamma-Glu-Cys-Gly)
Free thiols have extremely high reactivity toward __neutrophilic/electrophilic___ intermediates
Thiols intercept the reactive intermediates of alkylating agents
Free thiol levels > _#__-fold higher in alkylating agent-resistant cells
Increased expression of cellular _________________ (GST)
>GST’s are a family of Phase _____ metabolic enzymes – P1-1 is key ________
>GST catalyzes the reaction of ___________ with alkylating agents (parent drugs as well as reactive intermediates)
Increased
increased
glutathione
Glutathione
electrophilic
10 fold
glutathione S-transferase
II
isozyme
glutathione
To block hemorrhagic cystitis, Mesna is coadministered with which drug?
A. Methotrexate
B. Cyclophosphamide
C. Cisplatin
D. Mitomycin C
B. Cyclophosphamide
Which of the following is NOT a crosslinker?
A. Cytarabine
B. Cyclophosphamide
C. Carboplatin
D. Chlorambucil
A. Cytarabine
