Alkylating Agents & Platinum Compounds (Dykhuizen) Flashcards
What are alkylating agents?
drugs that generate reactive electrophilic intermediates that react with nucleophilic groups on DNA and proteins, resulting in the attachment of an aryl group
What is the most common site of alkylation?
guanine N7
The most effective anti-cancer drugs are ________ alkylating agents.
bifunctional
What two processes does cross-linking inhibit?
DNA replication and transcription
Are akylating agents cell cycle phase specific?
no
What compound was used by doctors in the 1940s to treat leukemia and lymphoma?
sulfur mustard (mustard gas)
Alkylating agents are potent __________.
electrophiles
What is the difference between intrastrand and interstrand cross-linking?
intrastrand = same strand
interstrand = separate strands
What happens if glutathione in cells reacts with alkylating agents?
it quenches their activity, inactivating them
Besides DNA bases, what else do alkylating agents react with?
- thiols
- amines
- cysteine and lyseine residues in proteins
- glutathione
When in the cycle are cells more susceptible to DNA alkylation?
late G1 and S phases (although still considered to be non-specific)
What is the most notable side effect of DNA alkylation?
second malignancies
What types of DNA damage can cross-linkers cause?
- preventing replication or transcription
- mispairing
- DNA fragmentation
What other names does mechlorethamine go by?
- Mustargen
- Mustine
- Chlormethine
What are the side effets of mechlorethamine?
- myelosuppression
- nausea/vomiting
- carcinogenic and teratogenic
In order to reduce reactivity and increase selectivity of nitrogen mustards, one method is to decrease the nucleophilicity of nitrogen. How is this done?
by adding aryl groups
What three compounds are aryl mechlorethamine derivatives?
- chlorambucil
- bendamustine
- melphalan
How does adding an aromatic ring to nitrogen mustards reduce nucleophilicity?
it pulls electron density away from the nitrogen, ultimately making it less reactive
What is the prodrug mechlorethamine derivative?
cyclophosphamide
What is the activating step for cyclophosphamide?
hydroxylation by hepatic cytochrome P450
In cyclophosphamide, what metabolite cross-links DNA?
phosphoramide mustard (PM)
True or false: cyclophosphamide’s hydroxylated metabolite can be converted to PM outside of the tumor cell.
false; it is highly polar and does not readily diffuse into cells, so it must be converted inside the tumor
What inactivates cyclophosphamide’s hydroxylated metabolite?
aldehyde dehydrogenase
What accounts for reduced bone marrow toxicity in cyclophosphamide compared to other agents?
elevated aldehyde dehydrogenase in some bone marrow progenitor cells
What side effects are associated with cyclophosphamide?
- mild bone marrow toxicity
- hemorrhagic cystitis (acrolein is toxic to bladder mucosa)
Which drug is known to have a longer half-life than cyclophosphamide, but also has increased CNS toxicity?
ifosfamide
What is mesna primarily used for?
administered with cyclophosphamide to block hemorrhagic cystitis
How does mesna help block hemorrhagic cystitis associated with cyclophosphamide?
its free thiol reacts with and inactivates acrolein metabolites
What component of mesna allows it to NOT penetrate cells?
a charged (anionic) sulfonate group
True or false: mesna does not accumulate in the urine.
false
Which of the following is a prodrug: mechlorethamine, cyclophosphamide, mesna, or chlorambucil?
cyclophosphamide
Give two examples of nitrosoureas.
- bis-chloroethylnitrosourea (BCNU) (Carmustine)
- Lomustine
What characteristic of nitrosoureas makes them indicated for glioblastoma multiforme and other brain tumors?
they are highly lipophilic and readily cross the BBB
What toxicity is most prevalent with nitrosoureas?
bone marrow toxicity (delayed and prolonged)
What dosing decision should be made when thinking about nitrosoureas’ delayed and prolonged myelosuppression?
requires longer interval between doses than other agents
Give an example of an alkyl sulfonate.
busulfan
What is busulfan indicated for?
given in high doses with cyclophosphamide before a bone marrow transplant to eradicate all hematopoeitic cells
What is the limiting toxicity of busulfan?
pulmonary fibrosis (“busulfan lung”)
What type of compound is mitomycin C (Mutamycin)?
arizidine-containing natural product
What is the dose-limiting toxicity of mitomycin C?
myelosuppression
Give an example of a mono-alkylating agent.
temozolamide (or, less commonly, dacarbazine)
TMZ utilizes which highly reactive methylating agent?
methyldiazonium ion
What processes does temozolamide inhibit?
DNA, RNA, and protein synthesis
True or false: TMZ can be combined with other alkylating agents.
true
What toxicities are most prevalent with temozolamide?
- milder bone marrow toxicity
- severe nausea/vomiting
What is TMZ indicated for?
brain cancers
What compound can make TMZ less effective and lead to resistance?
MGMT
What process typically silences MGMT?
DNA methylation
How can we predict whether glioblastoma patients will respond to TMZ?
looking at promoter methylation…if unmethylated, there is no point in giving TMZ
Do platinum drugs cross-link, alylate, or both?
cross-link (covalently)
What geometry does cisplatin have?
cis geometry
Cisplatin undergoes ________ ___________ in aqueous solution.
reversible hydrolysis
Equilibrium favors ________ in plasma, and ________ inside the cell.
cisplatin; aquo form
The aquo form of cisplatin reacts primarily at which two DNA sites?
guanine N7 and adenine N7
Because of bond lengths and angles, cisplatin cross-links are often _________.
intrastrand
What is cisplatin indicated for?
many solid tumors
What is the side effect profile for cisplatin?
- dose-limiting nephrotoxicity (proximal tubule)
- severe nausea/vomiting (centrally mediated)
- minimal bone marrow toxicity
- peripheral neuropathy related to cumulative dose
- ototoxicity
What are the three general mechanisms for alkylating and platinum drug resistance?
- increased expression of DNA repair enzymes
- increased intracellular concentration of non-protein thiols (esp. glutathione)
- increased expression of GST
