Alkylating Agents

Question 1

Classes of DNA alkylating agents

Answer 1

1. Nitrogen mustards –> cyclophsophamide, ifosfamide, mechlorethamine, melphalan
2. Alkyl sulfonates –> Busulfan
3. Nitrosoureas –> Carmustine and Lomustine
4. Triazenes –> Dacarbazine
5. Hydrazines –> Procarbazine
6. Platinum drugs –> Cisplatin and carbaplatin

Question 2

Alkylating agents attach to what atom on guanine?

Answer 2

N7; most nucleophilic nitrogen due to planar lone pair and lack of steric hindrance

Question 3

How do alkylating agents kill cancer cells?

Answer 3

Alkylating agents overwhelm the DNA repair machinery due to the rapid rate of DNA synthesis and cells die

Question 4

4 main nitrogen mustards?

Answer 4

Cyclophosphamide, ifosfamide, mechlorethamine, and melphalan

Question 5

Nitrogen mustard alkylating agent that requires metabolic activation (2)

Answer 5

Cyclophosphamide, Ifosfamide

Leads to unique mechanism of resistance –> down regulation of enzymes that convert to active form

Question 6

Unusual toxicities of cyclophosphamide (4)

Answer 6

1) Lung fibrosis,
2) renal failure,
3) urotoxicity (hemorrhagic cystitis),
4) CHF

Question 7

Drug given with cyclophosphamide to prevent hemorrhagic cystitis (urotoxicity)

Answer 7

Mesna –> acrolein is breakdown product of cyclophosphamide. Acrolein complexed by mesna to prevent toxic action

Question 8

Melphalan unusual toxicities

Answer 8

Lung fibrosis

Question 9

Alkyl sulfonates

Answer 9

Busulfan

Question 10

Busulfan unique toxicities (2)

Answer 10

1) Veno-occlusive disease of the liver –> increased by coincident CYP inhibitors.
2) Asthenia and hypotension resembling Addison’s disease

Question 11

Nitrosoureas

Answer 11

Carmustine (BCNU) and Lomustine (CCNU)

Question 12

Unique mechanism of BCNU/carmustine

Answer 12

Carbamoylate proteins and alkylate DNA –> little cross-resistance with other DNA alkylating agents

Question 13

Unique property of BCNU and CCNU

Answer 13

Lipophilic and non-ionized –> can cross BBB to enter CNS

Question 14

BCNU (carmustine) unique toxicities

Answer 14

Hepatic veno-occlusive disease, CNS dysfunction; seizures, dementia

Question 15

BCNU (carmustine) unique toxicities –> HE CORRECTED THIS LATER

Answer 15

CNS dysfunction; seizures, dementia

Question 16

Platinum drugs

Answer 16

Cisplatin, carboplatin

Question 17

Cisplatin/carboplatin mechanism

Answer 17

INTRAstrand DNA cross-linking of guanine –> disrupts DNA replication and transcription –> induces apoptosis

Question 18

Unique toxicities of cisplatin

Answer 18

Ototoxicity (kills hair cells of inner ear –> tinnitus (archer)), renal toxicity, and peripheral neuropathy

Question 19

Rescue therapy used with cisplatin

Answer 19

1-2L of forced hydration and amifostine (cytoprotective agent, free radical scavenger)

Question 20

Dose-limiting toxicity of carboplatin

Answer 20

Peripheral neuropathy

Question 21

Drug in Triazene class

Answer 21

Dacarbazine

Question 22

Dacarbazine mechanism

Answer 22

Methylation of DNA –> can see resistance with removal of methyls

Question 23

Drug in hydrazine class

Answer 23

Procarbazine –> requires metabolic activation

Question 24

Unusual toxicities of procarbazine

Answer 24

Weak monoamine oxidase inhibitor and nausea/headache while drinking alcohol
Causes male infertility

Question 25

Cancer resistance mechanisms

Answer 25

1. Increased DNA repair (alkylating and cisplatin) 2. Thiol trapping agents (alkylating, bleomycin, and cisplatin) 3. Decreased drug accumulation through p-gp pumps

Question 26

Treatment of acute emesis from chemo

Answer 26

Seretonin receptor antagonist, neurokinin-1 (NK-1) antagonist, and corticosteroids

Question 27

2 drugs given and their actions to prevent tumor lysis syndrome

Answer 27

Allopurinol--> inhibit Xanthine oxidase | Rasburicase--> convert uric acid to more soluble Allantoin

Question 28

Is cardiomyopathy (CHF) from Cyclophosphamide permanent or reversible? (long term or short term?)

Answer 28

reversible when the drug is removed (no long term consequences if survive initial bout)

Question 29

What specifically from Cyclophosphamide creates hemorrhagic cystitis?

Answer 29

Acrolein

Question 30

What CYP activates cyclophosphamide?

Answer 30

CYP2B

Question 31

Why is it so advantageous that Cyclophosphamide can be given PO?

Answer 31

because alkylating agents can cause a vesicant reaction (damage the endothelium) upon IV administration

Question 32

What alkylating agents have CNS toxicity?

Answer 32

Ifosfamide- causes altered mental status, ataxia, and seizures Carmustine (BCNU)- convulsions and encephalopathy

Question 33

What 2 alkylating agents can cause Renal toxicity?

Answer 33

Cyclophosphamide and Ifosfamide

Question 34

What alkylating agents cause pulmonary dysfunction?

Answer 34

Cyclophosphamide, Melphalan, and Busulfan (but all show some amount of pulm tox)

Question 35

Which alkylating agents show renal toxicity?

Answer 35

Cyclophosphamide, Ifosfamide, Cisplatin, Carboplatin

Question 36

Which of the platinum drugs has the worst renal toxicity?

Answer 36

Cisplatin

Question 37

Only nitrogen mustard given orally

Answer 37

cyclophosphamide (Wiki says melphalan can be oral too)

Question 38

what is unique about platinum drug peripheral neuropathy?

Answer 38

they accumulate in the ganglion cells and induce apoptosis