Fitzy 5: Alkylating Agents and cell cycle non-specific drugs Flashcards
Are cycle non-specific drugs dose dependent or schedule dependent?
dose dependent*
What do the DNA damaging drugs do?
they alkylate DNA
What are the Triazenes?
Dacarbazine
procarbazine
temozolomide
What do the triazenes do?
DNA alkylation
- methylation (bolded)
- Guanosine O6,N7
TU of triazenes?
- dacarazine: metastatic melanoma
- procarbazine: malignant glioma
- Temozolomide: treatment resistant glioma and astrocytoma
What are the nitrosoureas?
carmustine
lomustine
Streptozocin (red and bolded)
What do the nitrosoureas do?
DNA alkylation
- Alkylation then cross-linking
- guanosine O6, N7
- protein carbamoylation
- Streptozocin is selective at islet B cells***
TU of nitrosoureas?
- carmustine: brain tumors, lymphoma, melanoma
- Lomustine: brain tumors, lymphoma, melanoma
TU of Streptozocin?
insulinomas….
What does streptozocin cause?
diabetes
What are the nitrogen mustards?
cyclophosphamide ifosfamide mechlorethamine (vesicant.. this was bolded red)* melphalan chlorambucil busulfan estramustine
What doe the Nitrogen mustards do?
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
What are the uses of the Nitrogen mustards?
Mechlorethamine (vesicant): historical... MOPP regimen in lymphoma Melphalan: multiple myeloma Chlorambucil: CLL Busulfan: FML Estramustine: advanced prostate cancer
What are the bifunctional agents (the aziridines)?
thiotepa
mitomycin C
Altretamine
What do the aziridines do?
G-G crosslinks
TU of thiotepa
Breast, ovarian, bladder cancer
TU of mitomycin C?
breast and GI cancer
TU of altretamine
recurrent ovarian cancer resistant to other alkylating agents
What is the sensitivity to these drugs inversely proportional to?
the activity of repair enzymes (OAT and MGMT)
What are the nitrogen mustards again?
- mechlorethamine
- cyclophosphamide
- ifosfamide
- estramustine
What happens with mechlorethamine?
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
MOA of cyclophsphamide and ifosfamide?
-liver enzymes activate it
-the active drug is phosphoramide mustard plus acrolein
-
What causes hemorrhagic cystitis associated with cyclophosphamide?
Acrolein
What can acrolein be removed?
by administering MESNA with no change in therapeutic effect
What happens with ifosfamide that is different from cyclo?
the neurotoxicity
-other than that, it’s pretty much the same
What is MESNA analogous to?
GSH….. if given prophylactically, it will react with acrolein and diminish its toxic effect in the bladder
What is a special use for nitrogen mustards?
castration-resistant prostate cancer
What drug did we talk about to use for castration resistant prostate cancer?
estramustine
What is the risk in using estramustine?
arterial and venous thromboembolic events
What is the benefit of using estramustine?
anti-androgenic effects
What are the nitrosoureas?
Carmustine
Lomustine
Streptozocin
What are the dual actions of Nitrosoureas?
DNA alkylation
protein carbamoylation
Which nitrosoureas penetrate the CNS?
Carmustine and lomustine
- lipophliic nature favors good distribution into the CNS
- limited use outside of brain cancers
What is the toxicity with Carmustine and lomustine?
myelosuppression
How are Carmustine and lomustine administered?
Carmustine is IV
Lomustine is PO
What is the catch with DNA alkylation?
it can be repaired
-so the DNA repair rate determines the damage and clinical efficacy
What does DNA alkylation lead to?
inter-strand cross linking
What enzyme do we have to stop to make the nitrosoureas work better?
O6-Alkylguanine methyltransferase
What does Carmustine wafers help with?
Glioblastoma multiforme
What are the triazenes?
Dacarbazine
Temozolomide
Procarbazine
How is Dacarbazine activated?
- administered IV
- CYP450 activation
- MTIC is activated metabolite
How is Temozolamide activated?
- administered PO
- Spontaneous H+ activation
- MTIC is activated metabolite
What is so special about temozolamide?
it penetrates the CNS
- used for refractory anaplastic astrocytoma and glioblastmoa
- Dacarbazine doe NOT penetrate CNS effectively
What influences the efficacy of temozolomide?
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
What is a biomarker for temozolomide efficacy?
epigenetic silencing of MGMT
What are the cisplatin drugs?
cisplatin
carboplatin
oxaloplatin
TU of Cisplatin
-testicular cancer;ovarian cancer; NSCL
TU of carboplatin
ovarian cancer
TU of Oxaloplatin
Colorectal cancer
Toxicity of Cisplatin
renal
severe nausea/vomiting
otoxicity: acoustic nerve damage
Toxicity of carboplatin
neutropenia
toxicity of oxaloplatin
neturopenia
neuropathy-cold induced***
Cisplatin distinction?
- platinum-Cl complex
- stable in plasma and high Cl milieu
- hydrolyses in cell to activate agent
- complex elimination due to cell uptake
Carboplatin distinction
- more stable analog
- primarily renal elimination
oxaloplatin distinction
complex elimination due to cell uptake
What do these platin’s do?
form intra and inter strand cross links
How do the platins enter cells?
diffusion and CU2+ transporter
Why is there so much nephrotoxicity with cisplatin?
because the concentration of platinum achieved in the renal cortex is several-fold greater than that in plasma and other organs
What is the biggest severe side effect of cisplatin?
nephrotoxicity
How can cisplatin resistance come about?
- decreased uptake or increased efflux
- neutralization by GSH
- increased DNA repair
- defective apoptosis
What does the nephrotoxicity of cisplatin look like clinically?
- seen after 10 days of administration
- lower glomerular filtration rate
- higher serum creatinine
- reduced serum Mg and K
