Antimetabolites

Folate antagonists, fluoropyrimidines, cytidine analogs, purine analogs, and hypomethylating agents

5-FU = 5-fluorouracil  ·  ALL = acute lymphoblastic leukemia  ·  AML = acute myeloid leukemia  ·  ara-C = cytarabine  ·  CLL = chronic lymphocytic leukemia  ·  DHF = dihydrofolate  ·  DHFR = dihydrofolate reductase  ·  DPD = dihydropyrimidine dehydrogenase  ·  FCR = fludarabine, cyclophosphamide, rituximab  ·  FdUMP = fluorodeoxyuridine monophosphate  ·  HMA = hypomethylating agent  ·  MDS = myelodysplastic syndrome  ·  MTX = methotrexate  ·  THF = tetrahydrofolate  ·  TPMT = thiopurine methyltransferase  ·  TS = thymidylate synthase  ·  XO = xanthine oxidase

Methotrexate: Mechanism and Rescue
Mechanism
DHFR Inhibition & Polyglutamation
  • MTX blocks DHFR: DHF cannot be reduced to THF
  • THF depletion → halts thymidylate and purine synthesis
  • Polyglutamation by FPGS traps MTX intracellularly for weeks
  • Polyglutamates also directly inhibit TS and purine synthesis enzymes
  • S-phase specific; cycle-dependent exposure required
Safety
High-Dose MTX Hazards
  • NSAIDs + PPIs: reduce renal MTX clearance → 2–10× higher levels
  • Third-space fluids (ascites, effusions): drain before high-dose MTX
  • Leucovorin rescue: begins 24–42 h after MTX; continue until MTX < 0.1 μmol/L
  • Glucarpidase: reserved for severe toxicity or failed leucovorin rescue
  • Pemetrexed: requires folic acid + vitamin B12 pre-supplementation
5-Fluorouracil: Schedule-Dependent Toxicity
Feature Bolus 5-FU Continuous Infusion 5-FU
Dominant mechanism RNA disruption (FUTP incorporation) TS inhibition (FdUMP ternary complex)
Dose-limiting toxicity Myelosuppression Mucositis, hand-foot syndrome
Leucovorin benefit Less pronounced Stabilizes ternary complex; ~2× response rate
DPD role DPD catabolizes >85% of 5-FU; deficiency → life-threatening toxicity at standard doses
Cytidine Analogs and Purine Analogs: Key Points
Cytidine Analog
Cytarabine (ara-C)
  • S-phase specific: 7-day continuous infusion in AML induction
  • Activated by deoxycytidine kinase; resistance = loss of deoxycytidine kinase
  • High-dose ara-C: cerebellar toxicity (ataxia) — check neuro before each cycle
  • Indication: AML induction and consolidation
Cytidine Analog
Gemcitabine
  • Self-potentiating: diphosphate inhibits ribonucleotide reductase → less competition for DNA polymerase
  • Indications: pancreatic cancer, NSCLC, bladder, ovarian
  • Toxicity: thrombocytopenia, pulmonary toxicity, rare hemolytic uremic syndrome
Purine Analog
Fludarabine & Cladribine
  • Fludarabine: CLL (FCR regimen); profound CD4 depletion months to years
  • Cladribine: hairy cell leukemia; single 7-day course → >90% complete remission
  • Both require PCP and herpesvirus prophylaxis throughout and after therapy
  • Fludarabine: stop immediately if autoimmune hemolytic anemia develops
Pharmacogenomics: Two Mandatory Pre-Treatment Screens
Before 6-Mercaptopurine
TPMT Status
  • Low TPMT (~0.3%): 10–20% of standard dose; standard dose = fatal aplasia
  • Intermediate TPMT (~10%): 30–50% dose reduction
  • Allopurinol (XO inhibitor) + 6-mercaptopurine: fourfold level rise → aplasia; reduce to 25%
Before 5-FU or Capecitabine
DPD Status
  • Complete DPD deficiency: fatal toxicity within days of first dose
  • Partial deficiency (~3–5%): severe grade 3–4 toxicity in ~25–30%
  • DPYD genotyping or plasma uracil level recommended before first dose
  • Capecitabine + warfarin: inhibits CYP2C9 → INR rises; monitor weekly