Antimetabolites

Question 1

Azathioprine,

6-mercaptopurine

Answer 1

Class: antimetabolites

MOA: Purine (thiol) analogs
--> ↓ de novo purine synthesis.
Activated by HGPRT.
Azathioprine is metabolized
into 6-MP.

Clinical use: Preventing organ rejection,
rheumatoid arthritis, IBD,
SLE; used to wean patients
off steroids in chronic disease
and to treat steroid-refractory
chronic disease.

Adverse effects: Myelosuppression; GI, liver
toxicity.
Azathioprine and 6-MP are
metabolized by xanthine
oxidase; thus both have  risk
of toxicity with allopurinol or
febuxostat.

Question 2

Cladribine

Answer 2

Class: antimetabolites

MOA: Purine analog –> multiple
mechanisms (eg, inhibition
of DNA polymerase, DNA
strand breaks).

Clinical use: Hairy cell leukemia

Adverse effects: Myelosuppression,
nephrotoxicity, and
neurotoxicity.

Question 3

Cytarabine
(arabinofuranosyl
cytidine)

Answer 3

Class: antimetabolites

MOA: Pyrimidine analog –> DNA
chain termination. At higher
concentrations, inhibits DNA
polymerase

Clinical use: Leukemias (AML), lymphomas

Adverse effects: Myelosuppression with
megaloblastic anemia.
CYTarabine causes
panCYTopenia.

Question 4

5-fluorouracil

Answer 4

Class: antimetabolites

MOA: Pyrimidine analog bioactivated
to 5-FdUMP, which
covalently complexes with
thymidylate synthase and
folic acid. Capecitabine is a
prodrug.
This complex inhibits
thymidylate synthase
--> ↓ dTMP --> ↓ DNA
synthesis.

Clinical use: Colon cancer, pancreatic
cancer, actinic keratosis, basal
cell carcinoma (topical).
Effects enhanced with the
addition of leucovorin

Adverse effects: Myelosuppression, palmarplantar
erythrodysesthesia
(hand-foot syndrome).

Question 5

Methotrexate

Answer 5

Class: antimetabolites

MOA: Folic acid analog that
competitively inhibits
dihydrofolate reductase
--> ↓ dTMP --> ↓ DNA
synthesis

Clinical use: Cancers: leukemias
(ALL), lymphomas,
choriocarcinoma, sarcomas.
Non-neoplastic: ectopic
pregnancy, medical
abortion (with misoprostol),
rheumatoid arthritis, psoriasis,
IBD, vasculitis

Adverse effects: Myelosuppression, which is
reversible with leucovorin
“rescue.”
Hepatotoxicity.
Mucositis (eg, mouth ulcers).
Pulmonary fibrosis.
Folate deficiency, which
may be teratogenic (neural
tube defects) without
supplementation.
Nephrotoxicity.