Alkylating Agents

Question 1

Renal Toxicity Drugs

Answer 1

Cisplatin

Methotrexate

Question 2

Hepatic Toxicity Drugs

Answer 2

6-MP

Cyclophosphamide

Question 3

Pulmonary Toxicity Drugs

Answer 3

Belomycin

Question 4

Cardiac Toxicity Drugs

Answer 4

Doxorubicin

Daunorubicin

Question 5

Neurologic Toxicity Drugs

Answer 5

Vincristine
Cisplatin
Paclitaxel

Question 6

Immunosuppresive Toxicity Drugs

Answer 6

Cyclophosphamide

Methotrexate

Question 7

Bladder Toxicity Drugs

Answer 7

Cyclophosphamide

Question 8

Monofunction vs Bifunctional

Answer 8

 Bi: drug can bind to two different locations on the DNA; produce a cross-link that covalently links the strands of DNA; leads to the inability of the strands to separate so it cannot replicate further
 Mono: react with only one strand of DNA, introducing strand-breaking

Question 9

Are alkylating agents cell cycle specific or non-specific?

Answer 9

• CELL CYCLE NON-SPECIFIC
  o Bind directly to the DNA, particularly guanine
  o Nitrogen 7 is the guanine of target

Question 10

Nitrogen Mustard Agents

Answer 10

Mecloroethamine
Melphalan
Chlorambucil

Question 11

Phosphoramide mustards Agents

Answer 11

Cyclophosphamide

Itosphamide

Question 12

Triazenes Agents

Answer 12

Procarbazine

Temoxolomide

Question 13

Platinum Agents

Answer 13

Cisplatin
Carboplatin
Oxaaliplatin

Question 14

Monofunctional Agents

Answer 14

 Dacarbazine
 Procarbazine
 Temozolomide
Use: induce DNA strand breaks and mutations

Question 15

Bifunctional agents

Answer 15

	N2 Mustards
	Cyclophosphamide
	Nitrosureas
	Melphalan
Use: crosslink DNA, strand breaks and mutations

Question 16

Nitrogen mustard use

Answer 16

Mechlorethamine HCl: Hodgkin’s disease, lymphosarcoma

Melphalan: palliative treatments of multiple myeloma, ovarian cancer and some breast cancer

Question 17

Cyclophosphamide Use

Answer 17

lymphomas, solid tumors (breast, ovarian, lung)

Immunosuppressive so used in transplants and RA

Question 18

Difference between cyclophophamide and ifosphamide

Answer 18

C; Has 2 Chlorines on one side of the molecule

I: Has 2 chlorines on different sides of the molecule (decrease nephrotoxicity)

Question 19

Chlorambucil

Answer 19

Nitrogen mustard
 Use: Leukemia and lymphomas
 LEAST TOXIC OF ALL MUSTARD GASES

Question 20

Chlorambucil SE

Answer 20

SEVERE bone marrow suppression (neutropenia/myelosuppression), teratogenic (use contraceptives)
LEAST toxic of all mustard gases

Question 21

Phosphoramide Mustards MOA

Answer 21

PRODRUGS!!!
 Metabolized in the liver to give alkylating moieties
 Acrolein is the toxic form
 Phosphoramide mustard is the active form

Question 22

Anything you can do about the acrolein with phosphoramide mustards?

Answer 22

Can be neutralized by mercaptoethanesulfonate to prevent toxic effects

Question 23

Aziridine Use and MOA

Answer 23

 Use: adenocarcinoma of the breast or ovary, urinary bladder papillary carcinoma
 MOA: disrupts DNA via ethylenimine radical

Question 24

Aziridine SE

Answer 24

Renal, hepatic, myelosuppression

Question 25

Nitrosoureas Use and SE

Answer 25

 Use: BRAIN cancer
• Highly lipophilic and cross the BBB easily
 SE: hematopoietic

Question 26

Busulfan Use and SE

Answer 26

 Use: DOC for CML (leukemia)

 SE: myelosuppression

Question 27

Mitomycin Use and MOA

Answer 27

 Use: none given

 MOA: forms DNA cross-links between G-G

Question 28

Mitomycin SE

Answer 28

 SE: myelosuppression, stomatitis, diarrhea

 VESICANT (skin blisters)

Question 29

Hydrazine/Triazine Use

Answer 29

 Use: brain tumors

 Monofunctional; analogous to nitrosoureas

Question 30

***Side effect to ALL alkylating agents

Answer 30

o	Hematopoietic toxicity (bone marrow)
o	GI toxicity
o	Alopecia
o	Teratogenic
o	Immunosuppressive

Question 31

***Mechanism of resistance to alkylating agents

Answer 31

o Glutathione: react and inactivates all alkylating agents
o Glutathione S-transferases (GSTs) catalyze enzymatic conjugation of GSH with alkylating agents and these are over expressed in cancers
o ENHANCED DNA REPAIR IN DNA REPAIR IS ALSO A RESISTANCE MECHANISM