Antimetabolites

Question 1

Methotrexate

Answer 1

MOA: folic acid analog binds to DHFR and TS

Metabolized in cell with polyglutamate, disrupting folate metabolic pathway

IV or intrathecal

Reversed by leucovorin

ASA, NSAIDs, and penicillin inhibit renal excretion

Tox: myelosuppression, mucositis, diarrhea

Pemetrexed is specific for NSCLC (adeno)

Question 2

Mechanisms of MTX Cellular Resistance

Answer 2

Decreased drug transport

Decreased formation of cytotoxic MTX polyglutamates

Increased levels of target enzyme DHFR

Altered DHFR protein with reduced MTX affinity

Question 3

5-FU

Answer 3

Prodrug, metabolites first inhibits DNA synth, then RNA processing and translation

Inhibits TS

IV

Tox can occur if DPD is low

Myelosuppression, GI, neurotic, HAND-FOOD SYNDROME

Question 4

Capecitabine

Answer 4

EXTRA pro drug of 5-FU

ORAL

Tox
HAND-FOOT SYNDROME
DIARRHEA

NO ALOPECIA

Applications: breast and CRC

Question 5

Cytarabine (Ara-C)

Answer 5

S-phase specific antimetabolite

Inhibits DNA pol; chain terminator

IV, clears rapidly

EXCLUSIVELY HEMATOLOGIC; AML and LYMPH MENINGITIS

Tox:
GI and PANCYTOPENIA

Question 6

Gemcitabine

Answer 6

MOA: inhibits DNA pol, blocks repair, chain term

Application:
NSCLC
Pancreatic
Bladder
Ovarian
NHL lymphoma

Tox:
Neutropenia, GI, HEMOLYTIC UREMIC SYNDROME

Question 7

6-Mercaptopurine

Answer 7

Metabolized by HGPRT inhibits purine synth

Deactivated by xanthine oxidase (thus use allopurinol)

TPMT deficiency–> tox–> myelosuppression and diarrhea

Question 8

Cladribine and Fludaribine

Answer 8

Tx for CLL and NHL; cause myelosuppression and CD4/CD8 immunosuppression