Cytidine Analogs Flashcards
What percentage of plasma drug concentration is achieved within the CNS when Cytarabine is given as a CRI? A. 20-40% of plasma concentration B. ~50 of plasma concentration C. 200% of plasma concentration D. Cytarabine does not cross the blood brain barrie
a.
What is the mechanism responsible for radiosensitization with gemcitabine administration? A. Incorporation of gemcitabine metabolites into DNA B. Increased topoisomerase II expression following gemcitabine administration C. Gemcitabine inhibits DNA methylation D. Gemcitabine inhibits ribonucleotide reductase
d. Cytosar does B, DNA methylation is inhibited by azacitidine analogs.
Which drug, when used in combination with cytosine arabinoside, would result in inhibition of the hENT1? a. Cisplatin b. Masitinib c. Etoposide d. Hydroxyurea e. Methotrexate
b. hENT1 is a nucleoside transporter responsible for uptake of cytosine arabinoside into cells. Receptor tyrosine kinase inhibitors (incl masitinib, sutent) have been shown to inhibit hENT1, which may result in resistance to Ara-C. The other chemotherapeutics listed have all been used in combination with Ara-C and have potential synergistic activity.
Which enzyme catalyzes the rate-limiting step of cytosine arabinoside cytotoxicity (also thought to be a mechanism of drug resistance)? a. Deoxycytidine kinase b. Deoxycytidine monophosphate kinase c. Nucleoside diphosphate kinase d. Cytidine deaminase e. Deoxycytosine monophosphate deaminase
a. Abbreviations: a. CdR kinase; b. dCMP kinase; c. NDP kinase; d. CR deaminase; e. dCMP deaminase. Answers a, b, and c are involved in Ara-C activation (conversion to ara-CTP); however, CdR kinase is the rate-limiting step. Answers d and e are degradation enzymes.
Which organ system exhibits the lowest concentrations of cytidine deaminase? a. Plasma b. Granulocytes c. Gastrointestinal tract d. Liver e. Brain
e. Cytidine deaminase is responsible for deamination of Ara-C The brain and CSF contain very low levels of this enzyme, which allows Ara-C to reach high concentrations in the CNS.
What is the primary inactive metabolite of cytosine arabinoside? a. Uracil arabinoside b. Acrolein c. Deoxycytodine kinase d. 5-azauracil
a. Seventy to eighty percent of a given dose is excreted in the urine as ara-U, which, within minutes of drug injection, becomes the predominatnt compound found in plasma. Ara-U has a longer half-life in plasma than doses ara-C and may enhance the activation of ara-C through feedback inhibition of ara-C deamination in leukemic cells. Acrolien is the metabolite of cyclophosphamide Deoxycytodine kinase is an enzyme that metabolizes ara-C, so therefore it is not a metabolite 5-azauracil is one of many metabolites of 5-azacytadine found in dogs, p.182
Which of the following have been described as possibilities of tumor resistance to cytosine arabinoside? i. Overexpression BCL-2 and BCL-XL ii. Decreased activity of deoxycytodine kinase iii. Hyperphosphorylation of the AP-1 transcription factor iv. Dihydrofolate reductase gene polymorphism a. iv b. i, iv c. i, ii, iii d. iii, iv
c.
Cytosine arabinoside has its greatest toxic effects during which phase of the cell cycle? a. M phase b. G1 phase c. G2 phase d. S phase
d. As an inhibitor of DNA synthesis, ara-C has its greatest cytotoxic effects during the S phase of the cell cycle perhaps because of the requirement for its incorporation into DNA and the greater activity of anabolic enzymes during the S phase.
Which of the following hypothetical immunohistochemical stains for the following protein when POORLY expressed would cause resistance to gemcitabine? a. hENT equilibrative nucleoside transporter b. consentrive nucleoside transporter c. glutathione d. perioxidase e. thymidylate synthase
a. Low expression would lead to a decreased influx of gemcitabine into the cells
Which of the following when overexpressed would create resistance to cytosine arabinoside? a. Fas b. ATM c. Bcl-2 d. caspase 8 e. DNA polymerase alpha
c.
Which of the following dose prescriptions would be most appropriate the achieve the most rapid steady state plasma concentrations in a patient receiving cytosine arabinoside? a. 50mg/m2 SQ q12h x 4 doses b. 200mg/m2 IV as a CRI over 4 hours c. 75mg/m2 IV bolus followed by 125mg/m2 over 4 hours d. 50mg/m2 PO q 12h x 4 doses e. 50mg/m2 IP q12h x 4 doses
c. To accelerate the achievement of a steady-state concentration, one may give bolus dose of three time the hourly infusion rate before infusion. Owing to the presence of high concentrations of cytidine deaminase in the GI mucosa and liver, orally administered ara-C provides a much lower plasma levels than does direct IV administration.
Which of the following enzymes are involved in metabolism of cytosine arabinoside to its active form? i. nucleoside diphosphate kinase ii. deoxycitidine monophosphate kinase iii. deoxycitidine kinase iv. nucleoside monophosphate kinase a. i, ii, iii b. ii, iii, iv c. i, ii, iv d. i, iii, iv
a. There are three enzymes involved in conversion to the active metabolite, and those are the correct three enzymes. (iv) is another name for nucleoside phosphate kinase, which is involved in converting ADP to ATP and vice versa.
Which of the following are potential consequences of treatment with cytosine arabinoside? i. decreased repair of UV-light-induced DNA damage ii. apoptosis in both normal and malignant cells iii. increased genetic instability (recombination and crossover events) iv. decreased repair of gamma-radiation-induced DNA strand breaks a. i b. i + ii c. i, ii, + iii d. i, ii, iii, + iv
d. Cytosar treatment can cause all of the following. The genetic instability is caused by reiteration of DNA segments during replication. Both that and (i) are a result from inhibition of DNA pol alpha. (iv) is caused by inhibition of DNA pol beta, which occurs with less frequency than DNA pol alpha.
A crossover study of 6 healthy dogs compared cytosar when administered as a 50 mg/m2 subcutaneous injection versus a CRI of 25 mg/m2/hour for 8 hours. Plasma concentrations of cytosar were analyzed afterward via HPLC. Which of the following was a finding of the study? a. Dogs who received the subcutaneous administration never achieved steady state plasma levels of cytosar. b. There was no significant difference between the times it took each administration route to reach steady state. c. The CRI achieved steady state faster than the subcutaneous route, but the subcutaneous route maintained steady state longer. d. Both routes achieved steady state in similar times but the subcutaneous route maintained steady state longer.
a.
