Chemo Lecture 5: Alkylating Agents

Question 1

Cell cycle specific drugs are 1 dependent and cell cycle nonspecific drugs are _ 2_ dependent.

Answer 1

1. Schedule. The duration and timing of drug administration affect efficacy more than the dose
2. Dose. The amount administration affects the efficacy more than duration and and timing. These drugs are affective against tumor cells that are even in G0 phase

Question 2

_ drugs either cross link DNA or insert a methyl or ethyl group into DNA

Answer 2

Alkylating agents

Question 3

Which DNA alkylating agents causes methylation?

Answer 3

Triazenes: Dacarbazine, Procarbazine and temozolamide

Question 4

Which DNA alkylating agent causes alkylation then cross-linking and can also cause protein carbamoylation

Answer 4

Nitrosoureas: Carmustine and Lomustine

Question 5

Therapeutic use of Dacarbazine

Answer 5

Metastatic melanoma

Question 6

Therapeutic use of procarbazine

Answer 6

malignant glioma

Question 7

therapeutic use of temozolomide

Answer 7

Treatment resistant glioma and astrocytoma

Question 8

Therapeutic use of carmustine and lomustine

Answer 8

Brain tumors, lymphomas and melanoma

Question 9

Therapeutic use of streptozocin

Answer 9

insulinomas, but causes diabetes

Question 10

which drugs are nitrogen mustards

Answer 10

Cyclophosphamide, ifosfamide and mechlorethamine 
Melphalan
Chlorambucil
Busulfan
Estramustine

Question 11

MOA of Cyclophosphamide and ifosfamide

Answer 11

Crosslinks DNA

Question 12

Historically what is mechlorethamine used for?

Answer 12

It’s part of the lymphoma regimen (MOPP)

Question 13

Therapeutic use of Melphalan

Answer 13

Multiple myeloma

Question 14

Therapeutic use of chlorambucil

Answer 14

CLL

Question 15

Therapeutic use of busulfan

Answer 15

CML

Question 16

Therapeutic use of estraustine

Answer 16

advanced prostate cancer

Question 17

DNA alkylation/cross-linking agents are cell cycle specific or nospecific?

Answer 17

Non-specific. That’s why they are dose dependent

Question 18

Alkylating agent sensitivity is inversely proportional to activity of _

Answer 18

repair enzymes such as guanine O6-alkyl transferase (OAT), methyl guanine methyl transferase (MGMT)

Question 19

How is drug resistance achieved with alkylating agents?

Answer 19

If cancer cells adapt by producing more glutathione or increasing DNA repair

Question 20

which drug has instantaneous activation by water upon infusion and can produce potent vesicant that blisters and necrose

Answer 20

Mechlorethamine as used in Hodgkin’s. This drug can a big problem if the vein is missed when injecting or if it’s infused too fast

Question 21

MOA of cyclophosphamide and ifosfamide

Answer 21

Liver CYP450 enzymes CYP2B6 and CYP3A4 activates the drug and produces the active drug and side product acrolein. Cyclosphomade’s active metabolite is phosphoramide mustand. ifosfamide’s active product is isophosphoramide mustard. The active drug then cross links DNA at guanine N7.

Question 22

what toxicity is associated with acrolein (a metabolite of cyclophospphamide and ifosfamide) and how is it treated?

Answer 22

production of acrolein which causes hemorrhagic cystitis. It can be treated with MESNA (sulhydryl agent); when given prophylactically it will react with acrolein and diminish its toxic effect in the bladder

Question 23

What unique toxicity is associated with ifosfamide?

Answer 23

After liver metabolizes the drug chloroacetaldehyde is produced which is neurotoxic and causes altered mental status, seizures, paralysis, and coma

Question 24

What side effect is associated with MESNA

Answer 24

• Hypersensitivity reaction (pretreat with antihistamines, corticosteroids or both)
• N/V/GI distress

Question 25

What is estramustine used for?

Answer 25

castration-resistant prostate cancer

Question 26

Side effect of estramustine

Answer 26

Venous thromboembolism

Question 27

Dose limiting toxicity of carmustine and lomustine

Answer 27

myelosuppression

Question 28

MOA of nitrosoureas (carmustine and lomustine)

Answer 28

- DNA alkylation --> DNA damage | - Protein carbamoylation --> RNA and protein damage

Question 29

The efficacy of carmustine depends on _ and how can efficacy be increased?

Answer 29

DNA repair rate by quanine O-alkyltransferase. O6-alkylguanine methyltransferase inhibitors increases the efficacy by inhibiting he direct reversal pathway of DNA repair

Question 30

Both dacarbazine and temozolamide are activated to form what product?

Answer 30

MTIC

Question 31

Which Triazenes have good distribution into CNS and used for what cancers?

Answer 31

Temozolomide and thus is used for refractory anaplastic astrocytoma and glioblastoma

Question 32

what enzyme repairs DNA damage produced by temozolomide?

Answer 32

O6-MGMT. Thus the status of O6-MGMT enzyme in tumor influences the efficacy of temozolamide

Question 33

Some pts are HIGHLY susceptible to temozolomide, why?

Answer 33

Epigenetic silencing of MGMT

Question 34

which patients are best candidates for retreatment with temozolomide?

Answer 34

Pts who relapse after completion of adjuvant temozolomide and whose tumors have an epigenetically silenced DNA methyltransferase

Question 35

List the organoplatinum drugs

Answer 35

- cisplatin - carboplatin - oxaloplatin

Question 36

Therapeutic use of Cisplatin

Answer 36

- Testicular cancer - ovarian cancer; - NSCL

Question 37

Therapeutic use of carboplatin

Answer 37

Ovarian cancer

Question 38

Therapeutic use of oxaloplatin

Answer 38

Colorectal cancer (part of the FOLFOX regimen)

Question 39

Dose limiting tox of cisplatin

Answer 39

- nephrotoxicity (drug concentrates in renal cortex) --> acute renal failure - severe N/V - ototoxicity - acoustic nerve damage (can be irreversible)

Question 40

Dose limiting tox of oxaloplatin

Answer 40

- Neutropenia | - Neuropathy - cold induced

Question 41

MOA of cisplatin and related compounds

Answer 41

Enters cells by diffusion and CU2+ transporter. Once inside Cl atoms in cisplatin are replaced by H20 and this reacts with glutathione. Cisplatin-DNA intrastrand crosslinks results in cytotoxicity

Question 42

Mechanism of cisplatin resistance

Answer 42

1. decreased uptake or increased efflux of cisplatin 2. Neutralization of cisplatin by glutathione 3. increased DNA repair 4. defective apoptosis