DNA Cross-Linking Agents II Flashcards
What (3) toxic compounds are generated in the metabolism of Nitrosourea via the vinyl diazotic acid pathway? Which metabolite is the main alkylator of DNA?
- acetaldehyde
- isocyanate
- 2-Chloroethyl carbocation (MAIN ALKYLATOR)
*acetaldehyde + isocyanate are generated via the diazotic acid pathway
Explain how the 2-Chloroethyl carbocation metabolite, generated from metabolism of a nitrosourea, alkylates DNA?
2-Chloroethyl carbocation attaches (2) adjacent guanines through an ethyl linkage on the SAME STRAND
True or False - alkylation of DNA on the same strand is more difficult to repair than alkylation of DNA on two different strands?
False - alkylation of DNA on same strand is EASIER to repair
What compound is necessary for the decomposition of nitrosoureas?
H2O
All of the following regarding Carmustine are true, except?
A. highly lipophilic
B. can be administered IV or biodegradable wafer
C. IV administration must be diluted with ethanol
D. wafers are very stable at room temperature
E. used in brain tumors and blood cancers
(D) Carmustine wafers must be stored in the refrigerator since it is a low melt solid
Which of the following statements regarding nitrosoureas is incorrect?
A. Lomustine is more stable than Carmustine
B. Thrombocytopenia and leukopenia are common SE’s
C. Lomustine is orally available and via wafer
D. Pulmonary toxicity SE is seen after the 1st Tx
E. Seizures are a common SE of nitrosourea wafers
(D) pulmonary toxicity is a delayed reaction seen only after several rounds of chemotherapy with Carmustine and Lomustine
*pulmonary toxicity is also dose related
Which of the following statements is true?
A. Streptozocin has good water solubility B. Procarbazine is orally available C. Dacarbazine is orally available D. Both A & B E. None of the above
(D) Steptozocin is administered IV so yes, it does have good water solubility AND Procarbazine is orally available
*Dacarbazine is administered IV
What would you monitor for safety in patients taking Streptozocin?
Kidney function - this drug is nephrotoxic b/c kidney cells have same type of receptors (for the sugar moiety) and use similar transporters so these cells are very sensitive to this drug and can be killed
True or False - procarbazine generates a diazomethane metabolite?
True
*So does Dacarbazine and Temozolomide. Remember, diazomethane is a reactive intermediate that will methylate DNA, introducing a mutation so the G will pair with T instead of C leading to cell destruction
MOA: “O-6 methylation of guanine nucleotides”
What is needed for the metabolism of procarbazine?
oxygen
What (2) major metabolites are generated from metabolism of Procarbazine? Indicate which is the major reactive DNA methylator and which is the major urinary metabolite?
- Diazomethane - methylates guanine
- N-Isopropylterephthalamic acid - excreted in urine
*Diazomethane methylation of guanine results in guanine pairing with thymine (instead of cytosine) which will lead to apoptosis if not repaired
Why would resistance to Procarbazine be seen in patients with upregulated repair mechanisms?
Procarbazine is metabolized to diazomethane which introduces a methyl group to guanine. This can easily be repaired in cancers with upregulated repair mechanisms and thus the drug is less effective in killing cancer
Which alkylator can have significant drug-drug and drug-food interactions b/c of inhibition of MAO and enzymes involved in ethanol metabolism?
Procarbazine b/c it inhibits monoamine oxidase
*it also inhibits enzymes involved in ethanol metabolism - so patients can’t drink any booze
All of the following DNA alkylators are orally available except?
A. Procarbazine B. Lomustine C. Dacarbazine D. Temozolomide E. Busulfan
(C) Dacarbazine is NOT orally available; it is administered IV
All of the following anti-cancer agents can be administered IV except?
A. Busulfan B. Carmustine C. Streptozocin D. Cisplatin E. Satraplatin
(E) Satraplatin is orally available
*Busulfan can be administered orally OR IV
Which DNA alkylator is used in the Tx of malignant melanoma?
Dacarbazine
Which DNA alkylator is used in the Tx of glioblastoma and astrocytoma?
Temozolomide
All of the following are true regarding the metabolism of triazenes, except?
A. CYP’s are involved in Dacarbazine metabolism but not Temozolomide
B. AIC and diazomethane are the main metabolites
C. Temozolomide is safer than Dacarbazine
D. Toxic formaldehyde is generated from metabolism of Temozolomide
E. Diazomethane is the main alkylator
(D) Formadlehyde is generated from metabolism of DACARBAZINE and significantly contributes to its toxicity
Metabolism of Temozolomide is non-enzymatic and therefore does not produce toxic formaldehyde
True or False - More Dacarbazine is excreted unchanged in the urine than Temozolomide?
True
40% of Dacarbazine is excreted unchanged while
6% of Temozolomide is excreted unchanged
All of the following are prodrugs except?
A. Procarbazine B. Dacarbazine C. Temozolomide D. Altretamine E. Both A & D
(E) only DACARBAZINE and Temozolomide are PRODRUGS
Why is Temozolomide less toxic than Dacarbazine?
Temozolomide is metabolized non-enzymatically and therefore does NOT produce formaldehyde.
What is the major urinary metabolite of triazines? How does this metabolite contribute to triazine MOA?
Triazines: Dacarbazine and Temozolomide major urinary metabolite is AIC
AIC interferes with purine biosynthesis in cancer cells
All of the following contribute to anti-cancer MOA of Dacarbazine, except?
A. production of formaldehyde B. alkylation by diazomethane C. Interference with cancer cell purine biosynthesis D. none of the above E. all of the above
(E) all contribute toward anti-cancer MOA
Which of the following regarding Altretamine is true?
A. causes GI problems and peripheral nerve damage
B. majority of anti-cancer activity through production of multiple formaldehyde cross-linking DNA
C. Iminium ion metabolite alkylates DNA causing more damage to cancer cells
D. B & C only
E. All of the above
(E) all of the above
