Anti-Metabolites

Question 1

Anti-Metabolites (General Properties)

Answer 1

Block BP synthesis thereby blocking DNA synth

Have Max. effect at S-Phase

Question 2

Cellular Resistance to Anti-Metabolites

Answer 2

• Decreased drug transport
• MTX- decreased synth. of cytotoxic polyglutamates
• Increased level of target enzymes with DHFR
• Change in DHFR protein with decreased MTX affinity

Question 3

Methotrexate

Answer 3

Folic Acid Analog, Anti-Folate
- Binds/inhibits DHFR and TS– MTX polyglutamates selectively retained in cancer cells
- IV or intrathecal admin
- Dose adjust for renal insufficiency b/c renal excretion– ASA, penicillin, NSAIDS inhibit renal excretion
Tox:
- Myelosuppression– neutropenia, thrombocytopenia
- Mucositis, Diarrhea

Question 4

Leucovorin

Answer 4

• Reduced folate, reverses biologic effects of MTX

Question 5

Pemetrexed

Answer 5

Anti-Foloate

• Inhibits both pyrimidine (TS) and purine (GARFT) synth generating polyglutamate metabolites
• Renal excretion
• Myelosuppression
• Skin Rash
• Diarrhea, Mucositis, Fatigue
• Treatment for NSCLC (Adenocarcinoma)

Question 6

5-Fluorouracil

Answer 6

Fluoro-Pyrimidines
- Parent form inactive- active metabolites
- FdUMP inhibits TS– thymineless death of DNA
- FdUTP– inhibits DNA
- FUTP– inhibits RNA processing and translation
- IV Admin
- 85% catabolized by DPD, low/absent DPD can cause severe life threatening toxicity
Tox: - Hand &Foot syndrome with continuous infusion
- N/V, Diarrhea, Mucositis
- Neurotoxicity
- Myelosuppression

Question 7

Capecitabine

Answer 7

Pro-Pro Drug of 5-Fu
- Orally available, active metabolites generated in liver
- Metabolites converted to 5-FU in the tumor
Tox: Hand & Foot syndrome
- Diarrhea
- Treatment for breast and CRC

Question 8

Cytarabine (Ara-C)

Answer 8

Deoxycytadine Analog
- S Phase specific (Ara-SEE) anti-metabolite, competitively inhibits DNA pol.- ARA CTP incorporated into DNA
- IV admin- cleared very rapidly, need nearly constant infusion
- Tx for hematologic malignancies
- 1st line tx for AML in combo w/ idarubicin
- Liposomal version- tx for lymphomatous meningitis
Tox: - N/V, diarrhea, mucositis
- Myelosuppression, pancytopenia

Question 9

Gemcitabine

Answer 9

Deoxycytadine Analog (GemCYTabine)
- Inhibits DNA pol., blocks DNA and RNA synth/repair, chain terminator
- Treatment for broad range of malignancies
- Neutropenia
- N/V, Flu- Like symptoms
Rare Tox: HUS + renal microganiopathy

Question 10

6-Mercaptopurine

Answer 10

Purine (triol) analog
- Inactive parent molec. metabolized by HGPRT
- Inhibits purine synthesis
MercaptoPURaLLOL
- 6-MP deactivated in a rxn catalyzed by XO- allopurinol can cause excessive tox. since it inhibits XO
- TPMT deficiency assoc w/ severe toxicity– myelosuppression, diarrhea

Question 11

Cadiribine

Answer 11

Purine Analog
- Inhibits DNA synth. and repair, inhibits ribonucleotide reductase- incorporated into DNA and induces Apop
- Tx for CLL and NHL
Tox: Myelosuppression, N/V
- Immunosuppression- low CD4/CD8 cells

Question 12

Fludaribine

Answer 12

• Same mech as cladiribine
• Tx for CLL and NHL
  Tox: - Myelosuppression
• Immunosuppression
• Fevers, arthralgias, myalgias