2015 Antineoplastics

Critical Facts IconCRITICAL FACTS II: Antimetabolites
(if med school is a Minnesota forest with millions of trees,
these are the red pines)

  1. Antimetabolites are analogues of folate, pyrimidines or purines that interfere with key enzymes used during DNA synthesis.  ALL of these agents are cell cycle specific (CCS), as their effects occur during S phase.  A common mechanism for the development of resistance to these agents is modification of the target enzymes.

  2. METHOTREXATE is a potent antineoplastic agent because it blocks both purine and thymidylate synthesis by inhibiting dihydrofolate reductase (DHFR).  Administration of LEUCOVORIN (“LEUCOVORIN RESCUE”) can selectively reduce the METHOTREXATE toxicity in normal cells, as well as decrease the development of resistance.

  3. 5-FLUOROURACIL and CAPECITABINE decrease the biosynthesis of pyrimidine nucleotides by inhibiting thymidylate synthase, the enzyme that catalyzes the rate limiting step in DNA synthesis.  This results in the “thymineless death” of rapidly growing cells.

  4. 6-MERCAPTOPURINE and 6-THIOGUANINE must be activated by HGPRT to T‑IMP and 6‑thioGMP.  T-IMP and 6-thioGMP are poor substrates for guanylyl kinase, therefore IMP and GMP accumulate, causing “pseudofeedback inhibition” of PRPP synthetase (PRPS), glutamyl amidotransferase (GPAT)HGPRT, and the enzymes responsible for generation of XMP and adenylsuccinate from IMP.

  5. TUMOUR LYSIS SYNDROME is caused by the sudden, rapid death of millions of cells - a particular problem in successful treatment of patients with leukemia or lymphoma. TLS results from the development of electrolyte and metabolic disturbances that can produce life-threatening complications (esp. hyperuricemia), if not managed appropriately.

No matter what combination of antineoplastic drugs is being administered, ALLOPURINOL (a xanthine oxidase inhibitor) is frequently used during chemotherapy of hematologic cancers to prevent hyperuricemia due to tumor cell lysis.  The nephrotoxicity and acute gout produced by excessive uric acid are prevented by co-administration of ALLOPURINOL with any chemotherapeutic agent that produces TLS.

Simultaneous administration of ALLOPURINOL and 6‑MERCAPTOPURINE results in excessive mercaptopurine toxicity (because 6-MP is metabolized by xanthine oxidase) unless the dose of 6-MP is reduced to 25-30% of normal.

Email: Dr. Janet Fitzakerley | ©2015 University of Minnesota Medical School Duluth | Last modified: 11-apr-15 9:39 AM