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Heme and Lymph Midterm > Fitzy 5: Alkylating Agents and cell cycle non-specific drugs > Flashcards

Fitzy 5: Alkylating Agents and cell cycle non-specific drugs Flashcards

1
Q

Are cycle non-specific drugs dose dependent or schedule dependent?

A

dose dependent*

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2
Q

What do the DNA damaging drugs do?

A

they alkylate DNA

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3
Q

What are the Triazenes?

A

Dacarbazine
procarbazine
temozolomide

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4
Q

What do the triazenes do?

A

DNA alkylation

  • methylation (bolded)
  • Guanosine O6,N7
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5
Q

TU of triazenes?

A
  • dacarazine: metastatic melanoma
  • procarbazine: malignant glioma
  • Temozolomide: treatment resistant glioma and astrocytoma
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6
Q

What are the nitrosoureas?

A

carmustine
lomustine
Streptozocin (red and bolded)

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7
Q

What do the nitrosoureas do?

A

DNA alkylation

  • Alkylation then cross-linking
  • guanosine O6, N7
  • protein carbamoylation
  • Streptozocin is selective at islet B cells***
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8
Q

TU of nitrosoureas?

A
  • carmustine: brain tumors, lymphoma, melanoma

- Lomustine: brain tumors, lymphoma, melanoma

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9
Q

TU of Streptozocin?

A

insulinomas….

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10
Q

What does streptozocin cause?

A

diabetes

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11
Q

What are the nitrogen mustards?

A 
cyclophosphamide
ifosfamide
mechlorethamine (vesicant.. this was bolded red)*
melphalan
chlorambucil
busulfan
estramustine
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12
Q

What doe the Nitrogen mustards do?

A

Cyclophosphamide and ifisfamide: crosslinks DNA, PO, Liver CYP450 activation
MEchlorethamine (vesicant): crosslinks DNA, spontaneous activation
MElphalan: targeted to phenylalanine transporters
Chlorambucil: oral drug
Busulfan: alkyl sulfonate
Estramustine: anti-androgen and alkylation

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13
Q

What are the uses of the Nitrogen mustards?

A 
Mechlorethamine (vesicant): historical... MOPP regimen in lymphoma
Melphalan: multiple myeloma
Chlorambucil: CLL
Busulfan: FML
Estramustine: advanced prostate cancer
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14
Q

What are the bifunctional agents (the aziridines)?

A

thiotepa
mitomycin C
Altretamine

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15
Q

What do the aziridines do?

A

G-G crosslinks

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16
Q

TU of thiotepa

A

Breast, ovarian, bladder cancer

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17
Q

TU of mitomycin C?

A

breast and GI cancer

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18
Q

TU of altretamine

A

recurrent ovarian cancer resistant to other alkylating agents

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19
Q

What is the sensitivity to these drugs inversely proportional to?

A

the activity of repair enzymes (OAT and MGMT)

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20
Q

What are the nitrogen mustards again?

A
  • mechlorethamine
  • cyclophosphamide
  • ifosfamide
  • estramustine
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21
Q

What happens with mechlorethamine?

A

instantaneous activation by water upon infusion

  • potnent vesicant can cause blisters, necrosis if extravastion occurs
  • It’s the “M” in MOPP regimen for Hodgkin’s disease
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22
Q

MOA of cyclophsphamide and ifosfamide?

A

-liver enzymes activate it
-the active drug is phosphoramide mustard plus acrolein
-

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23
Q

What causes hemorrhagic cystitis associated with cyclophosphamide?

A

Acrolein

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24
Q

What can acrolein be removed?

A

by administering MESNA with no change in therapeutic effect

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25
Q

What happens with ifosfamide that is different from cyclo?

A

the neurotoxicity

-other than that, it’s pretty much the same

26
Q

What is MESNA analogous to?

A

GSH….. if given prophylactically, it will react with acrolein and diminish its toxic effect in the bladder

27
Q

What is a special use for nitrogen mustards?

A

castration-resistant prostate cancer

28
Q

What drug did we talk about to use for castration resistant prostate cancer?

A

estramustine

29
Q

What is the risk in using estramustine?

A

arterial and venous thromboembolic events

30
Q

What is the benefit of using estramustine?

A

anti-androgenic effects

31
Q

What are the nitrosoureas?

A

Carmustine
Lomustine
Streptozocin

32
Q

What are the dual actions of Nitrosoureas?

A

DNA alkylation

protein carbamoylation

33
Q

Which nitrosoureas penetrate the CNS?

A

Carmustine and lomustine

  • lipophliic nature favors good distribution into the CNS
  • limited use outside of brain cancers
34
Q

What is the toxicity with Carmustine and lomustine?

A

myelosuppression

35
Q

How are Carmustine and lomustine administered?

A

Carmustine is IV

Lomustine is PO

36
Q

What is the catch with DNA alkylation?

A

it can be repaired

-so the DNA repair rate determines the damage and clinical efficacy

37
Q

What does DNA alkylation lead to?

A

inter-strand cross linking

38
Q

What enzyme do we have to stop to make the nitrosoureas work better?

A

O6-Alkylguanine methyltransferase

39
Q

What does Carmustine wafers help with?

A

Glioblastoma multiforme

40
Q

What are the triazenes?

A

Dacarbazine
Temozolomide
Procarbazine

41
Q

How is Dacarbazine activated?

A
  • administered IV
  • CYP450 activation
  • MTIC is activated metabolite
42
Q

How is Temozolamide activated?

A
  • administered PO
  • Spontaneous H+ activation
  • MTIC is activated metabolite
43
Q

What is so special about temozolamide?

A

it penetrates the CNS

  • used for refractory anaplastic astrocytoma and glioblastmoa
  • Dacarbazine doe NOT penetrate CNS effectively
44
Q

What influences the efficacy of temozolomide?

A

the status of the O6-MGMT enzyme in the tumor

  • methyl guanosine methyl transferase
  • it can repair DNA damage from temozolomide alkylating DNA… it’s bullshit
45
Q

What is a biomarker for temozolomide efficacy?

A

epigenetic silencing of MGMT

46
Q

What are the cisplatin drugs?

A

cisplatin
carboplatin
oxaloplatin

47
Q

TU of Cisplatin

A

-testicular cancer;ovarian cancer; NSCL

48
Q

TU of carboplatin

A

ovarian cancer

49
Q

TU of Oxaloplatin

A

Colorectal cancer

50
Q

Toxicity of Cisplatin

A

renal
severe nausea/vomiting
otoxicity: acoustic nerve damage

51
Q

Toxicity of carboplatin

A

neutropenia

52
Q

toxicity of oxaloplatin

A

neturopenia

neuropathy-cold induced***

53
Q

Cisplatin distinction?

A
  • platinum-Cl complex
  • stable in plasma and high Cl milieu
  • hydrolyses in cell to activate agent
  • complex elimination due to cell uptake
54
Q

Carboplatin distinction

A
  • more stable analog

- primarily renal elimination

55
Q

oxaloplatin distinction

A

complex elimination due to cell uptake

56
Q

What do these platin’s do?

A

form intra and inter strand cross links

57
Q

How do the platins enter cells?

A

diffusion and CU2+ transporter

58
Q

Why is there so much nephrotoxicity with cisplatin?

A

because the concentration of platinum achieved in the renal cortex is several-fold greater than that in plasma and other organs

59
Q

What is the biggest severe side effect of cisplatin?

A

nephrotoxicity

60
Q

How can cisplatin resistance come about?

A
  • decreased uptake or increased efflux
  • neutralization by GSH
  • increased DNA repair
  • defective apoptosis
61
Q

What does the nephrotoxicity of cisplatin look like clinically?

A
  • seen after 10 days of administration
  • lower glomerular filtration rate
  • higher serum creatinine
  • reduced serum Mg and K

Heme and Lymph Midterm (11 decks)

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