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

Question 1

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

Answer 1

dose dependent*

Question 2

What do the DNA damaging drugs do?

Answer 2

they alkylate DNA

Question 3

What are the Triazenes?

Answer 3

Dacarbazine
procarbazine
temozolomide

Question 4

What do the triazenes do?

Answer 4

DNA alkylation

• methylation (bolded)
• Guanosine O6,N7

Question 5

TU of triazenes?

Answer 5

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

Question 6

What are the nitrosoureas?

Answer 6

carmustine
lomustine
Streptozocin (red and bolded)

Question 7

What do the nitrosoureas do?

Answer 7

DNA alkylation

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

Question 8

TU of nitrosoureas?

Answer 8

• carmustine: brain tumors, lymphoma, melanoma

- Lomustine: brain tumors, lymphoma, melanoma

Question 9

TU of Streptozocin?

Answer 9

insulinomas….

Question 10

What does streptozocin cause?

Answer 10

diabetes

Question 11

What are the nitrogen mustards?

Answer 11

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

Question 12

What doe the Nitrogen mustards do?

Answer 12

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

Question 13

What are the uses of the Nitrogen mustards?

Answer 13

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

Question 14

What are the bifunctional agents (the aziridines)?

Answer 14

thiotepa
mitomycin C
Altretamine

Question 15

What do the aziridines do?

Answer 15

G-G crosslinks

Question 16

TU of thiotepa

Answer 16

Breast, ovarian, bladder cancer

Question 17

TU of mitomycin C?

Answer 17

breast and GI cancer

Question 18

TU of altretamine

Answer 18

recurrent ovarian cancer resistant to other alkylating agents

Question 19

What is the sensitivity to these drugs inversely proportional to?

Answer 19

the activity of repair enzymes (OAT and MGMT)

Question 20

What are the nitrogen mustards again?

Answer 20

• mechlorethamine
• cyclophosphamide
• ifosfamide
• estramustine

Question 21

What happens with mechlorethamine?

Answer 21

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

Question 22

MOA of cyclophsphamide and ifosfamide?

Answer 22

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

Question 23

What causes hemorrhagic cystitis associated with cyclophosphamide?

Answer 23

Acrolein

Question 24

What can acrolein be removed?

Answer 24

by administering MESNA with no change in therapeutic effect

Question 25

What happens with ifosfamide that is different from cyclo?

Answer 25

the neurotoxicity | -other than that, it's pretty much the same

Question 26

What is MESNA analogous to?

Answer 26

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

Question 27

What is a special use for nitrogen mustards?

Answer 27

castration-resistant prostate cancer

Question 28

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

Answer 28

estramustine

Question 29

What is the risk in using estramustine?

Answer 29

arterial and venous thromboembolic events

Question 30

What is the benefit of using estramustine?

Answer 30

anti-androgenic effects

Question 31

What are the nitrosoureas?

Answer 31

Carmustine Lomustine Streptozocin

Question 32

What are the dual actions of Nitrosoureas?

Answer 32

DNA alkylation | protein carbamoylation

Question 33

Which nitrosoureas penetrate the CNS?

Answer 33

Carmustine and lomustine - lipophliic nature favors good distribution into the CNS - limited use outside of brain cancers

Question 34

What is the toxicity with Carmustine and lomustine?

Answer 34

myelosuppression

Question 35

How are Carmustine and lomustine administered?

Answer 35

Carmustine is IV | Lomustine is PO

Question 36

What is the catch with DNA alkylation?

Answer 36

it can be repaired | -so the DNA repair rate determines the damage and clinical efficacy

Question 37

What does DNA alkylation lead to?

Answer 37

inter-strand cross linking

Question 38

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

Answer 38

O6-Alkylguanine methyltransferase

Question 39

What does Carmustine wafers help with?

Answer 39

Glioblastoma multiforme

Question 40

What are the triazenes?

Answer 40

Dacarbazine Temozolomide Procarbazine

Question 41

How is Dacarbazine activated?

Answer 41

- administered IV - CYP450 activation - MTIC is activated metabolite

Question 42

How is Temozolamide activated?

Answer 42

- administered PO - Spontaneous H+ activation - MTIC is activated metabolite

Question 43

What is so special about temozolamide?

Answer 43

it penetrates the CNS - used for refractory anaplastic astrocytoma and glioblastmoa - **Dacarbazine doe NOT penetrate CNS effectively**

Question 44

What influences the efficacy of temozolomide?

Answer 44

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

Question 45

What is a biomarker for temozolomide efficacy?

Answer 45

epigenetic silencing of MGMT

Question 46

What are the cisplatin drugs?

Answer 46

cisplatin carboplatin oxaloplatin

Question 47

TU of Cisplatin

Answer 47

-testicular cancer;ovarian cancer; NSCL

Question 48

TU of carboplatin

Answer 48

ovarian cancer

Question 49

TU of Oxaloplatin

Answer 49

Colorectal cancer

Question 50

Toxicity of Cisplatin

Answer 50

renal severe nausea/vomiting otoxicity: acoustic nerve damage

Question 51

Toxicity of carboplatin

Answer 51

neutropenia

Question 52

toxicity of oxaloplatin

Answer 52

neturopenia | neuropathy-cold induced***

Question 53

Cisplatin distinction?

Answer 53

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

Question 54

Carboplatin distinction

Answer 54

- more stable analog | - primarily renal elimination

Question 55

oxaloplatin distinction

Answer 55

complex elimination due to cell uptake

Question 56

What do these platin's do?

Answer 56

form intra and inter strand cross links

Question 57

How do the platins enter cells?

Answer 57

diffusion and CU2+ transporter

Question 58

Why is there so much nephrotoxicity with cisplatin?

Answer 58

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

Question 59

What is the biggest severe side effect of cisplatin?

Answer 59

nephrotoxicity

Question 60

How can cisplatin resistance come about?

Answer 60

- decreased uptake or increased efflux - neutralization by GSH - increased DNA repair - defective apoptosis

Question 61

What does the nephrotoxicity of cisplatin look like clinically?

Answer 61

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