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Heme and Lymph Midterm > Chemo Lecture 5: Alkylating Agents > Flashcards

Chemo Lecture 5: Alkylating Agents Flashcards

1
Q

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

A
  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
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2
Q

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

A

Alkylating agents

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3
Q

Which DNA alkylating agents causes methylation?

A

Triazenes: Dacarbazine, Procarbazine and temozolamide

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4
Q

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

A

Nitrosoureas: Carmustine and Lomustine

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5
Q

Therapeutic use of Dacarbazine

A

Metastatic melanoma

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6
Q

Therapeutic use of procarbazine

A

malignant glioma

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7
Q

therapeutic use of temozolomide

A

Treatment resistant glioma and astrocytoma

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8
Q

Therapeutic use of carmustine and lomustine

A

Brain tumors, lymphomas and melanoma

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9
Q

Therapeutic use of streptozocin

A

insulinomas, but causes diabetes

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10
Q

which drugs are nitrogen mustards

A 
Cyclophosphamide, ifosfamide and mechlorethamine 
Melphalan
Chlorambucil
Busulfan
Estramustine
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11
Q

MOA of Cyclophosphamide and ifosfamide

A

Crosslinks DNA

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12
Q

Historically what is mechlorethamine used for?

A

It’s part of the lymphoma regimen (MOPP)

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13
Q

Therapeutic use of Melphalan

A

Multiple myeloma

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14
Q

Therapeutic use of chlorambucil

A

CLL

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15
Q

Therapeutic use of busulfan

A

CML

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16
Q

Therapeutic use of estraustine

A

advanced prostate cancer

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17
Q

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

A

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

18
Q

Alkylating agent sensitivity is inversely proportional to activity of _

A

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

19
Q

How is drug resistance achieved with alkylating agents?

A

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

20
Q

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

A

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

21
Q

MOA of cyclophosphamide and ifosfamide

A

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.

22
Q

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

A

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

23
Q

What unique toxicity is associated with ifosfamide?

A

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

24
Q

What side effect is associated with MESNA

A
  • Hypersensitivity reaction (pretreat with antihistamines, corticosteroids or both)
  • N/V/GI distress
25
Q

What is estramustine used for?

A

castration-resistant prostate cancer

26
Q

Side effect of estramustine

A

Venous thromboembolism

27
Q

Dose limiting toxicity of carmustine and lomustine

A

myelosuppression

28
Q

MOA of nitrosoureas (carmustine and lomustine)

A
  • DNA alkylation –> DNA damage

- Protein carbamoylation –> RNA and protein damage

29
Q

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

A

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

30
Q

Both dacarbazine and temozolamide are activated to form what product?

A

MTIC

31
Q

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

A

Temozolomide and thus is used for refractory anaplastic astrocytoma and glioblastoma

32
Q

what enzyme repairs DNA damage produced by temozolomide?

A

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

33
Q

Some pts are HIGHLY susceptible to temozolomide, why?

A

Epigenetic silencing of MGMT

34
Q

which patients are best candidates for retreatment with temozolomide?

A

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

35
Q

List the organoplatinum drugs

A
  • cisplatin
  • carboplatin
  • oxaloplatin
36
Q

Therapeutic use of Cisplatin

A
  • Testicular cancer
  • ovarian cancer;
  • NSCL
37
Q

Therapeutic use of carboplatin

A

Ovarian cancer

38
Q

Therapeutic use of oxaloplatin

A

Colorectal cancer (part of the FOLFOX regimen)

39
Q

Dose limiting tox of cisplatin

A
  • nephrotoxicity (drug concentrates in renal cortex) –> acute renal failure
  • severe N/V
  • ototoxicity - acoustic nerve damage (can be irreversible)
40
Q

Dose limiting tox of oxaloplatin

A
  • Neutropenia

- Neuropathy - cold induced

41
Q

MOA of cisplatin and related compounds

A

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

42
Q

Mechanism of cisplatin resistance

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

Heme and Lymph Midterm (7 decks)

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