Alkylating Agents Flashcards
Alkylating agents are ______
DNA is ______
____ will “attack” ____
Alkylating agents are electrophilic
DNA is nucleophilic
DNA attacks alkylating agents & forms irreversible complex
6 Types of Alkylating Agents
- Nitrogen Mustards
- Aziridine Alkylators
- Nitrosoureas
- Alkyl Sulfonates
- Triazenes
- Methylhydrazines
Nitrogen Mustards [activation]
intramolecular nucleophilic attack to highly electrophilic active aziridinium ion
[triangle with charged N+]
Nitrogen Mustards [Stability]
reactive and unstable in water–> formulate in acidic medium to stabilize
Nitrogen Mustards [Following Alkylation]
After DNA damage–> repair mechanisms get activated; MGMT comes in and cleaves off pieces
Hoping that damage is sufficient enough –> repair mechanisms won’t work & cell dies
Nitrogen Mustards [drug names]
Cyclophosphamide
Ifosfamide
Chlorambucil
Bendamustine
Nitrogen Mustards [Cyclophosphamide Metabolic Activation]
Cyclophosphamide is a prodrug that needs to be converted to activate nitrogen mustard by CYP2B6
Toxic metabolite created– ACROLEIN; this is urotoxic and nephrotoxic
Nitrogen Mustards [PK]
CYP inducers/inhibitors have great effect on circulating levels of drug
Aldehyde dehydrogenase metabolizes to inactive form
Hepatic Elimination
Acrolein Toxicity
use MESNA [a charged drug product] to neutralize the acrolein and reduce uro/nephro-toxicity
Aziridine Alkylator [drug]
Thiotepa
Aziridine [ADE]
well tolerated– only myelosuppression
Nitrosoureas [drug]
Carmustine
Nitrosoureas [PK]
very lipophilic – cross BBB very easily
Alkyl Sulfonates [drug]
Busulfan
Alkyl Sulfonates [ADE]
Pulmonary Fibrosis (Busulfan)
Triazenes [MOA]
transfer methyl groups rather than ethyl groups
Triazenes [Mechanism of Resistance]
MGMT upregulation
Triazene [ADE]
increased risk of mutagenesis/carcinogenesis; methyl groups easier to surpass by DNA polymerases, and not as lethal – smaller changes can persist
CINV: Acute vs. Delayed
Chemo Induced Nausea/Vomiting
Acute: PNS activated– 5HT released in gut and activates vagus nerve
Delayed: CNS activated – CTZ causes substance P release –> activates NK1 receptors
Alkylating Agents [Mechanisms of Resistance]
Decreased transport into cell
Increased Intracellular nucleophilic substances – ex) glutathione; conjugates electrophilic intermediates –> no longer reactive
Enhanced DNA Repair pathways (MGMT)
Ineffective DNA Repair pathways –> Nucleotide excision repair and mismatch repair rely on recognition of the error – checkpoints have to work to induce apoptosis
Platinum Coordinating Agents [drugs]
Cisplatin
Carboplatin
Oxaliplatin
Cisplatin [Activation]
need HYDRATION x 2 –> occurs best at low [Cl] because of concentration gradient – replaces Cl with H2O molecules
Cisplatin [Neutralization]
Sodium thiosulfate
Chlorine replenishment
MOA – increase levels causes lower concentration gradient –> prevents conversion to active form and decreases adverse effects (HIGHLY nephrotoxic)
Differences in Pt coordinating agents
Oxaliplatin – bigger/bulkier so difficult to repair; doesn;t share resistance with cisplatin/carboplatin
Cisplatin– FASTER to form active form
Platinum coordinating agents [Mechanisms of Resistance]
cross-resistance between cisplatin and carboplatin
- decreased drug accumulation
- increased glutathione or sulfhydryl concentrations –> bind & inactivated drug
- changes in DNA repair mechanisms
Oxaliplatin additional MOA
Suppress thymidylate synthase expression –> synergistic effect with 5-FU
