Antineoplastics

Question 1

Methotrexate

Answer 1

folic acid analog that functions by binding and inactivating dihydrofolate reductase, the enzyme responsible for reducing folic acid to tetrahydrofolate

prevents the reduction of folic acid to tetrahydrofolate

Question 2

5-fluorouracil (5-FU)

Answer 2

pyrimidine analog that primarily functions to inhibit DNA synthesis by inhibition of thymidylate synthetase after enzymatic conversion to its nucleotide floxuridine monophosphate by any of a number of intracellular reactions.

Binds tetrahydrofolate and thymidylate synthetase in a stable-reaction intermediate form, thereby effectively decreasing the amount of thymidylate synthetase available for thymidine synthesis

requires the presence of reduced folate in order to form complexes with thymidylate synthetase

has a reduced cytotoxic effect in cells that are deficient in tetrahydrofolate.

Question 3

Leucovorin (N5-formyl-tetrahydrofolate)

Answer 3

tetrahydrofolate derivative that does not require reduction by dihydrofolate reductase before it can function as a cofactor for thymidylate synthase and other enzymes involved with purine and amino acid synthesis

Because it bypasses the dihydrofolate reductase step that is inhibited by methotrexate, it can be used to “rescue” normal cells from the toxicity of methotrexate

can be utilized to potentiate the toxicity of fluoropyrimidines such as fluorouracil by strengthening the association of the drug with thymidylate synthase.

Question 4

Cytarabine

Answer 4

pyrimidine analog antimetabolite that is incorporated into DNA leading to strand termination

Question 5

Gemcitabine

Answer 5

• another pyrimidine analog that functions much like cytarabine
• differs from cytarabine in that it is not S-phase specific, likely owing to additional cytotoxic functions such as inhibition of ribonucleotide reductase.

Question 6

Fludarabine

Answer 6

deamination-resistant purine nucleotide analog that exerts its cytotoxicity by many mechanisms, including inhibition of DNA polymerase, DNA primase, DNA ligase, and ribonucleotide reductase

treat chronic lymphocytic leukemia (CLL).

Question 7

6-mercaptopurine (6-MP) and 6-thioguanine (6-TG)

Answer 7

• cytotoxic purine analogs inhibit de novo purine synthesis.
• activated by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inactivated by xanthine oxidase (XO) and thiopurine methyltransferase
  (TPMT) in the liver.
• this is mainly because coadministration can lead to high levels of cytotoxic 6-MP metabolites (allopurinol does not impact 6-TG in the same manner).
• Some physicians prefer to assess TPMT enzyme activity levels in their patients before administering 6-MP
• 6-MP and azathioprine, a 6-MP prodrug, have also been used for treatment of inflammatory bowel disease.

Question 8

Cladribine

Answer 8

used in hairy cell leukemia treatment) is a cytotoxic purine analog resistant to degradation by ADA.
- Adenosine deaminase (ADA) converts adenosine to inosine as part of purine metabolism. This enzyme is deficient in severe combined immune deficiency but may be overexpressed in some malignancies.

Question 9

Anthracyclines (eg, doxorubicin, daunorubicin)

Answer 9

cardiotoxic chemotherapeutic agents. - can cause dose-related acute and chronic cardiac damage (eg, dilated cardiomyopathy).

• On biopsy, patchy fibrosis with vacuolization and lysis of myocytes are evident.