Fitzpatrick - Anti-Neoplastic Drugs, Alkylating Agents CCNSD Flashcards
Cell cycle specific drugs are dependent on what?
Schedule dependent - Duration and timing of drug administration affect efficacy»_space;> dose dependent
DNA alkylating/cross-linking agents: MOA
- MOA - attack nucleophiles (-06, -07 N7 position of guanine)
- Damage - crosslinking (bifunctional) or alkylating (monofunctional)
- Consequences - miscoding of DNA bases, DNA breakage
Name repair sensitive G-G crosslinks.
N-mustards, thiotepa, busulfan
Name repair sensitive G-C crosslink.
Chloroethylnitrosoureas
Name repair insensitive G-G crosslink.
Mitomycin
Name repair sensitive G-CH3 (O6-G-methylation).
Dacarbazaine, procarbazine, temozolomide
Cell cycle non-specific drugs are dependent on what?
Efficacy weighed more heavily on Dose Dependent»_space;> schedule
Therapeutic use for mechlorethamine
Hodgkin Disease (MOPPS)
Adverse effect of mechlorethamine.
Blisters, necrosis if extravasation occurs. Occurs bc instantaneous activation by water upon infusion.
Cyclophosphamide activation in ___ location via ___ enzyme.
In liver via CYP450 activation.
Metabolites of Cyclophosphamide (two).
- Acrolein = urotoxic (bladder)
- Phosphoramide Mustard = active tumor metabolite drug
Ifosfamide activation in ___ location via ___ enzyme.
In liver via CYP450 activation and CYP2B6/CYP3A4.
Metabolites of ifosfamide (three).
- Acrolein = urotoxic (bladder)
- Phosphoramide Mustard = active tumor metabolite drug
- Chloracetaldehyde (CYP2B6/CYP3A4) = NEUTROTOXICITY - seizures, paralysis, coma
Dose limiting toxicity of nitrosoureas.
myelosuppression
A person has brain cancer - what class of Alkylating agents should be used and why?
bc they penetrate/have Good distribution in the CNS.
- Carmustine (Nitrosoureas) limited to brain cancer
- Temozolomide (triazene) - refractory anaplastic astrocytoma and glioblastoma
MOA of dacarbazine and temozolomide
- Dacarbazine - IV w/ CYP4501A activation
- Temozolomide - PO; spontaneous H+
Both result in activated metabolite MTIC –> electrophile (CH3)
What triazene DOES NOT penetrates the CNS effectively?
Dacrabazine
Status of O^6 MGMT has what effects on temozolomide alkylating DNA
- High MGMT = DNA repair nullifies damage - refractory
- Low MGMT = susceptible dt catastrophic DNA damage = GOOD
How does cisplatin/related compounds enter cells to cross link?
Enter via diffusion and Cu2+ transporter
1/2 of cisplatin is excreted in urine in 24hrs, so ____ location has a greater concentration of platinum than plasma and other organs, thus causing ____.
Renal cortex
NEPHROTOXICITY
MOA of cisplatin resistance.
- Decreased uptake or increased efflux.
- Neutralization of cisplatin by GLUTATHIONE
- Increased DNA repair
4 Defective apoptosis
10 days after ___ drug administration, lower GFR, higher serum Cr, reduced serum Mg and K levels = ____
Cisplatin administration
Cisplatin nephrotoxicity (can also be secondary to tumor lysis syndrome)
oxaloplatin toxicity
neutropenia, cold induced neurpathy
