Hem-Onc: Antimetabolites

Question 1

Methotrexate (MTX): mech

Answer 1

S-phase specific
Folic acid analog that inhibits dihyrdofolate reductase
Decreases dTMP –> decreased DNA and protein synthesis

Question 2

Leucovorin (folinic acid): mech

Answer 2

bypasses metabolic block –> protects normal cells

Rescues methotrexate myelosuppression

Question 3

Methotrexate (MTX): uses

Answer 3

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

Question 4

Methrotrexate (MTX): tox

Answer 4

Myelosuppression, which is reversible with leucovorin (folinic acid) “rescue”
Macrovesicular fatty change in liver (hepatotoxic)
Mucositis (mouth ulcers)
Teratogenic
Pulmonary fibrosis

Question 5

5-fluorouracil (5-FU): mech

Answer 5

S-phase specific
Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid.
This complex inhibits thymidylate synthase –> decreased dTMP –> decreased DNA and protein synthesis

Question 6

5-FU: uses

Answer 6

Colon cancer, pancreatic cancer, basal cell carcinoma (topical).

Question 7

5-FU: tox

Answer 7

Myelosuppression, which is NOT reversible with leucovorin.
Overdose: “rescue” with uridine
Photosensitivity
Does not cause acute toxicity!

Question 8

Uridine rescues:

Answer 8

5-FU overdose

Question 9

Cytarabine (arabinofuranosyl cytidine): mech

Answer 9

S-phase specific

Pyrimidine analog –> inhibition of DNA polymerase

Question 10

Cytarabine (arabinofuranosyl cytidine): uses

Answer 10

Leukemias, lymphomas

Question 11

Cytarabine (arabinofuranosyl cytidine): tox

Answer 11

Leukopenia, thrombocytopenia, megaloblastic anemia.

“CYTarabine causes panCYTopenia”

Question 12

Azathioprine: mech

Answer 12

Purine (thiol) analogs –> decreased de novo purine synthesis
Acitvated by HGPRT

Question 13

Azathioprine: mech

Answer 13

Purine (thiol) analogs –> decreased de novo purine synthesis
Acitvated by HGPRT
Azathioprine is metabolized to 6-MP
S-phase specific

Question 14

Azathioprine: uses

Answer 14

Preventing organ rejection, RA, SLE (azathioprine).

Used to wean pts off steroids in chronic Dx and to tx steroid refractory dx

Question 15

Azathioprine: tox

Answer 15

Myelosuppression, GI, liver.
Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have increased tox with allopurinol or febuxostate, which inhibits their metabolism

Question 16

6-mercaptopurine (6-MP): mech

Answer 16

Purine (thiol) analog –> decreases de novo purine synthesis.
Activated by HGPRT
S-phase specific

Question 17

6-MP: uses

Answer 17

Preventing organ rejection, RA.
Leukemia, IBD (6-MP, 6-TG)
Used to wean pts off steroids in chronic dx and to tx steroid refractory dx.

Question 18

6-MP: tox

Answer 18

Myelosuppression, GI, liver.
Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have increased tox with allopurinol or febuxostat, which inhibits their metabolism

Question 19

6-thioguanine (6-TG): mech

Answer 19

Purine (thiol) analog –> decreased de novo purine synthesis.
Activated by HGPRT.
S-phase specific

Question 20

6-TG: uses

Answer 20

Preventing organ rejection, RA.
Leukemia, IBD (6-MP, 6-TG).
Used to wean pts off steroids in chronic dx and to tx steroid refractory dx.

Question 21

6-TG: tox

Answer 21

Myelosuppression, GI, liver.

Question 22

Cladribine (2-CDA): mech

Answer 22

Purine analog –> multiple mechanism (ex. inhibition of DNA polymerase, DNA breaks)

Question 23

Cladribine (2-CDA): uses

Answer 23

Hairy Cell Leukemia

Question 24

Cladribine (2-CDA): tox

Answer 24

Myelosuppression, nephrotoxicity, and neurotoxicity

Question 25

Cladribine (2-CDA): mech

Answer 25

Purine analog –> multiple mechanism (ex. inhibition of DNA polymerase, DNA breaks)
S-phase specific