Alkylating Agents and Platinum Compounds - Chemo Flashcards
what rescues a 5-FU overdose?
a) leucovorin
b) cytosine arabinoside
c) thymidine
d) methotrexate
thymidine
what increases the efficacy of 5-FU?
a) leucovorin
b) cytosine arabinoside
c) thymidine
d) methotrexate
leucovorin
which antimetabolite should not be given to pateints being treated for gout?
a) cytosine arabinoside
b) 6-mercaptopurine
c) cladribine
d) 5-FU
6-mercaptopurine
which anti-metabolite dose not directly inhibit DNA/RNA synthesis?
a) 5-FU
b) cytosine arabinoside
c) nelarabine
d) methotrexate
methotrexate
Alkylating Agents
- drugs that generate reactive ___ (electron deficient) intermediates and react with nucleophilic (electron rich) groups on DNA and proteins
- result in attachment of ___ (hydrocarbon) group to DNA and protein
- MOA: alkylation of ___ bases in DNA - guanine N7
- ___ inhibit DNA replication as well as transcription (NOT cell-cycle ___ - mess up every phase)
- ___ of cross-links in cancer cells is not efficient
- attempted replication of modified DNA can result in ___
- most effective anti-cancer drugs are bifunctional alkylating agents that produce ___ and ___ strand linkages
- electrophilic
- alkyl
- cross-links
- specific
- repair
- apoptosis
- intra, inter
Alkylating agents history - WWI
sulfur mustard gas
- soldiers were observed to have ___ suppression and ___ shrinkage
- first leukemia and lymphoma treatment in 1940s
- bone marrow, lymph node
nitrogen mustards are similar but are ___ , not ___
- very reactive and excessively ___
liquid, gas
- toxic
purine bases in DNA
all of the ring nitrogens have some reactivity, as well as the exocyclic oxygens. the nucleophilicity is controlled by steric, electronic, and hydrogen bonding effects
alkylating agents are potent
a) reducing agents
b) electrophiles
c) nucleophiles
d) oxidizing agents
electrophiles
Effects of DNA Alkylation
alkylating agents react with many nucelophiles other than DNA bases
- thiols and amines especially reactive
- cysteine and lysine residues in proteins
- protein adducts occasionally trigger an ___ response
- ____ in cells can react with alkylating agents and “ quench “ their activity.
toxicity to cancer cells results from DNA ___ and DNA ___
- DNA-protein cross-links also inhibit DNA function
cells are more susceptible in late
___ and ___ phases of the cell cycle by alkylaying agents are considered ___ ___
- allergic
- glutathione
- alkylation, crosslinking
- G1, S, non-cycle specific
cell cycle checkpoints and common chemotherapies
DNA damaging agents (Non-cycle specific)
- alkylators/platinum
- (5)
- Chlorambucil
- Cyclophosphamide
- Mitomycin C
- Cisplatin
- Radium-223
side effects of alkylation
some normal cell populations are rapidly ___ and therefore are sensitive to effects of DNA alkylation and cross-linking (bone marrow, gut mucosa)
monoadducts are mutagenic and carcinogenic
- measurable incidende of ___ ___ in long term survivors
- most arise in the ___ ___ (mostly leukemias)
- proliferating
- 2nd malignancies
- bone marrow
T or F: crosslinkers cause only one type on DNA damage
FALSE
Mechlorethamine (Mustargen, Mustine, Chlormethine)
first used clinically in the 1940s - not commonly used anymore
extremely reactive compound (t1/2 ~ 1min)
- rapidly alkylates all ___ - modifies DNA, RNA, and protein
- antitumor activity correlates with DNA ___
SE of all alkylators
- ___ suppression
- N/V
- ____ genic and ___ genic
- nucleophiles
- cross-links
- myelosuppression
- carcinogenic, teratogenic
Mechlorethamine Derivatives
Two strategies have been employed to reduce reactivity and increase selectivity of nitrogen mustards
1) decrease nucleophilicity of nitrogen by adding ___ groups
- examples: Chlorambucil, bendamustine, melphalan
- aryl
T or F: aryl groups increased nucleophilicity
FALSE; reduce nucleophilicity
“wait, why dose adding an aryl make it less reactive? I thought they were electrophiles?”
the aziridinium intermediate is the ___ group
- primary amines (better ___ ) form aziridinium intermediates much faster; therefore, they are more ___
- electrophilic
- nucleophiles
- reactive
Mechlorethamine Derivatives
Two strategies have been employed to reduce reactivity and increase selectivity of nitrogen mustards
2) prodrug strategy - cyclophosphamide
chemically stable prodrug - requires ___ by hepatic CYP450
- phosphoramide mustard (PM) is the metabolite that cross-links
- hydroxylated metabolite must be converted to PM in the tumor cells
- PM is highly ___ and does not readily diffuse into cells
- PM has a ___ t1/2
metabolite inactivated by aldehyde dehydrogenase
- elevated aldehyde dehydrogenase in some bone marrow progenitor cells accounts for ___ bone marrow toxicity
- hydroxylation
- polar
- short
- reduced
Cyclophosphamide
most useful and commonly used alkylating agent
SE modest compared to most agents
- mild bone marrow toxicity - sparing to marrow stem cells and platelets because of high ___ levels in these cell types
- hemorrhagic cyctitis - ___ is toxic to bladder mucosa
also in this class: ifosamide has longer t1/2 than cyclophosphamide but also has ___ CNS toxicity
- ADH
- acrolein
- increased
Mesna
cyclophosphamide is toxic to the bladder
- ___ accumulates in urine and damages bladder mucosa
mesna containing a charged anionic sulfonate group so it does not ___ cells
- anion transporters in proximal tubule excrete via kidney
- mesna accumulates in the ___ (and therefore in the bladder
- the free thiol on mesna reacts with and inactivates ___ metabolites in urine
- administered with cyclophosphamide to block hemorrhagic cystitis
- acrolein
- penetrate
- urine
- acrolein
Mitomycin C (Mutamycin)
- aziridine-containing natural product
- functions as an alkylating agent, although ___ pattern differs slightly from other alkylating agents
- ___ is dose limiting
- form ___ adducts (crosslinks)
- toxicity
- myelosuppression
- bifunctional
which of the following is a prodrug?
a) mechlorethamine
b) cyclophosphamide
c) mitomycin C
d) chlorambucil
cyclophosphamide
Platinum Drugs
- ___ crosslinkers, but not ___ agents
- cisplatin is the original prototype square planar complex with leaving groups having ___ geometry
- covalent, alkylating
- cis
Platinum drugs
cisplatin undergoes ___ hydrolysis in aqueous solution
- equilibrium favors cisplatin in ___ (where there is a ___ chloride concentration)
- equilibrium favors aquo form ___ cell ( ___ chloride concentration)
- aquo form is highly ___ and a potent electrophile. Reacts rapidly with other nucleophiles, especially thiols
also in this class:
- carboplatin
- oxaliplatin
- reversible
- plasma, high
- inside, low
- reactive
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 ___ strand
- ___ strand ___ - Pt cross link imposes severe geometrical constraints on DNA
- introduces sharp bend in cross-linked strand
- lesion NOT readily repaired by standard DNA repair ___
- guanine, adenine
- intrastrand
- intrastrand, cis
- enzymes
Cisplatin
highly effective agent for many solid tumors
- drug requires non- ___ conversion to the active aquo form
- aquo form produces primarily ___ strand cross-links
- crosslinks, form more ___ than other alkylating agents
- some tumor cells more sensitive in ___ than in ___ phase
SE profile very different from other alkylating agents:
- dose-limiting ___
- severe N/V
- ___ bone marrow toxicity (good in combo with other drugs)
- peripheral ___ - related to cumulative dose
- ototoxicity
- enzymatic
- intrastrand
- slowly
- G1, S
- nephrotoxicity
- minimal
- neuropathy
drug resistance - general mechanisms
___ expression of DNA repair enzymes
increased intracellular concentration of non-protein thiols, especially, ___
- glutathione is a ___ -containing tripeptide
- free thiol have extremely ___ reactivity toward electrophilic intermediates
- thiols intercept the reactive intermediates of alkylating agents
- free thiol levels are more than 10x ___ in alkylating agent resistant cells
___ expression of cellular glutathioe S-transferase (GST)
- GST’s are a family of phase II metabolic enzymes
- GST catalyzes the reaction of ___ with ___ agents (parent drugs as well as ractive intermediates)
- increased
- glutathione
- cysteine
- high
- higher
- increased
- glutathione, alkylating
