Alkylators Flashcards
Is dacarbazine bifunctional or monofunctional?
monofunctional
Is procarbazine bifunctional or monofunctional?
monofunctional
What is the dose-limiting toxicity of procarbazine when administered intravenously?
a. Hypersensitivity reactions
b. Myelosuppression
c. Gastrointestinal upset
d. Neurotoxicity
e. Reversible hepatic dysfunction
d. Neurotoxicity
Neurotoxicity is the dose-limiting toxicity when PCB is administered IV. It is characterized by drowsiness, depression, agitation, paresthesia. Contrary, the dose-limiting toxicity of oral PCB is myelosuppression. Interestingly, myelosuppression does not occur with high-dose IV bolus dosing. There is also a lack of clinical antitumor effect, emphasizing the importance of first-pass hepatic metabolism for activation of PCB to active intermediates. Hypersensitivity reactions, GI upset, and hypersensitivity-mediated hepatic injury can also occur. [Chabner, pg 296]
It has been hypothesized that cancer stem cells survive or become resistant to cyclophosphamide treatment due to which of the following?
a. Chloroacetaldehyde
b. Aldehyde dehydrogenase
c. Guanine O6-alkyl transferase
d. N-Isopropyl-P-formlybensamide
b. Aldehyde dehydrogenase
Increased aldehyde dehydrogenase activity, which converts aldophosphamide to the inactive carboxyphosphamide, was present in cells resistant to cyclophosphamide. (p.273) Resistance to cyclophosphamide may also be determined by the activity of cellular ALDH. ALDH is an enzyme responsible for the oxidation of intracellular aldehydes. (p. 274)
Which drug is routinely administered to patients receiving ifosfamide due to the slower activation rate resulting in prolonged exposure to the metabolite acrolein?
a. TEPA
b. Palonosetron
c. Neulasta
d. MESNA
d. MESNA
Because the slower activation rate of ifosfamide results in more prolonged exposure to the bladder toxic metabolite acrolein, the disulfide detoxifer MESNA is routinely administered in association with ifosfamide. (p. 281)
Which of the following case scenarios should be considered and may be contraindicated when prescribing procarbazine for this patient?
a. 8 yo FS Boxer on clomipramine for separation anxiety
b. 10 yo MN Labrador on Rimadyl for arthritis
c. 15 yo MI Pug on Optimmune for KCS
d. 5 yo FS Redbone Coonhound on levetiracetam for seizures
a. clomipramine
Because procarbazine undergoes extensive hepatic microsomal metabolism and because it inhibits monoamine oxidase, which is widespread in tissues and plasma, there are many potential drug-drug and drug-food interactions. Monoamine oxidase inhibition and pyridoxal phosphate depletion by procarbazine cause CNS depression. This inhibition of MOA also predisposes patients to acute hypertensive reactions after concomitant therapy with tricyclic antidepressants and sympathomimetic drugs. (p293-294) and Table 14B.2
Which of the following is correct regarding alkylating agents?
a. alkylating SN2 reactions occur by first order kinetics
b. alkylating SN1 reactions occur by second order kinetics
c. SN1 reactions depend on the concentration of the alkylating reagent solely
d. SN2 reactions depend on the concentration of the nucleophile solely
e. Up-regulation of MSH2 would increase the efficacy of alkylating reagents
c.
Sn1 reactions occur with first-order kinetics with a rate that depends solely on the concentration of the alkylating agent. In contrast, Sn2 reactions follow second-order kinetics and depend on the concentration of BOTH the alkylating agent and the nucleophile.
Which of the following could theoretically DECREASE uptake of mechlorethamine into the cell?
a. leucovorin b. MESNA c. glutathione d. choline e. L-lysine
d. choline
mechlorethamine uptake depends upon the choline transport system
High levels of leucine can inhibit uptake of melphalan. Others are primarily taken up by passive diffusion.
Which of the following is TRUE regarding dacarbazine?
a. Dacarbazine is poorly distributed to the cerebrospinal fluid
b. The most frequent toxic event after IV administration is myelosuppression
c. The primary mechanism of action is formation of phosphoramide mustard
d. The oral bioavailability is 100%
e. This drug is primarily excreted through the hepatobiliary system
Answer: A
B) most frequent is vomiting and diarrhea, C) exact mechanism is unkown but most evidence is toward O6-methylguanine formation D) 50% bioavailability E) primary excretion as 50% unchanged as DTIC through urine
Which of the following possesses inherent alkylating activity (does not require activation)?
a. cyclophosphamide b. chlorambucil c. ifosfamide d. procarbazine
b. chlorambucil
The others must be metabolized to active intermediates.
The oral bioavailability of cyclophosphamide in dogs is ___ of the intravenous dose.
a. 15%
b. 25%
c. 33%
d. 48%
b. 25%
Warry, E., et al. (2011). “Pharmacokinetics of cyclophosphamide after oral and intravenous administration to dogs with lymphoma.” J Vet Intern Med 25(4): 903-908.
Which potential metabolite of cyclophosphamide may cause neurotoxicity?
a. chloroacetaldehyde b. aldophosphamide c. carboxyphosphamide d. phosphoramide
a. chloroacetaldehyde
Which of the following statements is true regarding the mechanism of action of alkylating agents?
a. O-6 atom of guanine is the most vulnerable to alkylation by active metabolites of nitrogen mustards
b. Dacarbazine is a bifunctional alkylating agent
c. Bifunctional alkylating agents produce interstrand DNA cross-links that are responsible for their cytotoxic effects
d. Extracellular aldehyde dehydrogenase inactivates cyclophosphamide metabolites by converting aldophosphamide to phosphoramide mustard
Answer: C
- N-7 position of guanine is the most electronegative and therefore is most vulnerable to attach by aziridinium cation intermediate of the nitrogen mustards
- Dacabazine (and procarbazine) is a monofunctional alkylating compound that appears to induce cell death via the mismatch repair-mediated process
- Intracellular ALDH converts aldophosphamide to inactive carboxyphosphamide. Aldophosphamide undergoes spontaneous elimination to form phosphoramide mustard and acrolein
How does glutathione impact the pharmacodynamics of alkylating agents?
a. Glutathione competes with some alkylating agents for cellular transport
b. Glutathione functions to protect cells against toxic effects of alkylating agents.
c. Glutathione inhibits apoptosis of cells suffering from DNA alkylation
d. Glutathione is a cofactor of AKT, which together perform phosphorylation of proapoptotic proteins
Answer: b.
Page 277. GSH is involved in alkylating agent detoxification. Modulation of GSH concentrations within cells has been evaluated to reduce toxicity. Depletion of GSH has also been examined to decrease tumor resistance to alkylators, but proved too toxic clinically.
Concurrent use of which of the following drugs may cause you to use a higher dose of CCNU to maintain efficacy?
a. Phenobarbital b. Leveteracitam c. Leucine d. Ranitidine
Answer: a. Phenobarb
Enhancement of P450 activity in vivo by phenobarbital has been shown to abolish the therapeutic effect of BCNU against intracerebral rat tumor and decreased the therapeutic activity of CCNU and BCNU
