Alkylating Agents

Question 1

Alkylating agents are ______
DNA is ______
____ will “attack” ____

Answer 1

Alkylating agents are electrophilic
DNA is nucleophilic
DNA attacks alkylating agents & forms irreversible complex

Question 2

6 Types of Alkylating Agents

Answer 2

1. Nitrogen Mustards
2. Aziridine Alkylators
3. Nitrosoureas
4. Alkyl Sulfonates
5. Triazenes
6. Methylhydrazines

Question 3

Nitrogen Mustards [activation]

Answer 3

intramolecular nucleophilic attack to highly electrophilic active aziridinium ion

[triangle with charged N+]

Question 4

Nitrogen Mustards [Stability]

Answer 4

reactive and unstable in water–> formulate in acidic medium to stabilize

Question 5

Nitrogen Mustards [Following Alkylation]

Answer 5

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

Question 6

Nitrogen Mustards [drug names]

Answer 6

Cyclophosphamide
Ifosfamide
Chlorambucil
Bendamustine

Question 7

Nitrogen Mustards [Cyclophosphamide Metabolic Activation]

Answer 7

Cyclophosphamide is a prodrug that needs to be converted to activate nitrogen mustard by CYP2B6
Toxic metabolite created– ACROLEIN; this is urotoxic and nephrotoxic

Question 8

Nitrogen Mustards [PK]

Answer 8

CYP inducers/inhibitors have great effect on circulating levels of drug
Aldehyde dehydrogenase metabolizes to inactive form
Hepatic Elimination

Question 9

Acrolein Toxicity

Answer 9

use MESNA [a charged drug product] to neutralize the acrolein and reduce uro/nephro-toxicity

Question 10

Aziridine Alkylator [drug]

Answer 10

Thiotepa

Question 11

Aziridine [ADE]

Answer 11

well tolerated– only myelosuppression

Question 12

Nitrosoureas [drug]

Answer 12

Carmustine

Question 13

Nitrosoureas [PK]

Answer 13

very lipophilic – cross BBB very easily

Question 14

Alkyl Sulfonates [drug]

Answer 14

Busulfan

Question 15

Alkyl Sulfonates [ADE]

Answer 15

Pulmonary Fibrosis (Busulfan)

Question 16

Triazenes [MOA]

Answer 16

transfer methyl groups rather than ethyl groups

Question 17

Triazenes [Mechanism of Resistance]

Answer 17

MGMT upregulation

Question 18

Triazene [ADE]

Answer 18

increased risk of mutagenesis/carcinogenesis; methyl groups easier to surpass by DNA polymerases, and not as lethal – smaller changes can persist

Question 19

CINV: Acute vs. Delayed

Answer 19

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

Question 20

Alkylating Agents [Mechanisms of Resistance]

Answer 20

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

Question 21

Platinum Coordinating Agents [drugs]

Answer 21

Cisplatin
Carboplatin
Oxaliplatin

Question 22

Cisplatin [Activation]

Answer 22

need HYDRATION x 2 –> occurs best at low [Cl] because of concentration gradient – replaces Cl with H2O molecules

Question 23

Cisplatin [Neutralization]

Answer 23

Sodium thiosulfate
Chlorine replenishment

MOA – increase levels causes lower concentration gradient –> prevents conversion to active form and decreases adverse effects (HIGHLY nephrotoxic)

Question 24

Differences in Pt coordinating agents

Answer 24

Oxaliplatin – bigger/bulkier so difficult to repair; doesn;t share resistance with cisplatin/carboplatin

Cisplatin– FASTER to form active form

Question 25

Platinum coordinating agents [Mechanisms of Resistance]

Answer 25

cross-resistance between cisplatin and carboplatin

1. decreased drug accumulation
2. increased glutathione or sulfhydryl concentrations –> bind & inactivated drug
3. changes in DNA repair mechanisms

Question 26

Oxaliplatin additional MOA

Answer 26

Suppress thymidylate synthase expression –> synergistic effect with 5-FU