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Table 3-2

Pyrimidine Analogs

DRUG and COMMON INDICATIONSMECHANISM OF ACTIONCLINICAL POINTS
Cytarabine (ara-C)

  • AML
  • Acute lymphoblastic leukemia (ALL)
  • CML in blast crisis
  • CNS leukemia
  • Primary CNS lymphoma
  • NHL
Cytarabine mimics cytosine and is metabolized through the pathway below. Of note, Ara-U and Ara-UMP are inactive metabolites

Cytarabine affects DNA synthesis in the following ways:
  1. Inhibition of DNA polymerase A and B for replication and repair
  2. Incorporated into DNA to inhibit template function and chain elongation
  • Intravenous (IV) administration. Can also be given intrathecally for prevention or treatment of CNS leukemia/lymphoma
  • The majority of the dose (70%–80%) is excreted in urine. Dose adjustment in renal impairment advised, especially in the setting of high-dose ara-C (HiDAC)
  • Consider dose adjustment in severe hepatic impairment
  • Adverse events include at all doses:
    • Myelosuppression
    • Gastrointestinal toxicities (nausea/vomiting, mucositis, diarrhea)
    • Hepatic dysfunction (increased liver function tests [LFTs], intrahepatic cholestasis)
    • Cytarabine syndrome (fever, myalgia, bone pain, chest pain, rash)
    • Pancreatitis
    • Maculopapular rash
  • Adverse events include particularly at high doses (>1,000 mg/m2):
    • CNS→ acute cerebellar toxicity, unsteady gait, dementia, coma
    • Gastrointestinal: gastrointestinal (GI) ulcer, pancreatitis, peritonitis
    • Ocular: conjunctivitis or keratitis. Corneal deposits presenting as photophobia, foreign body sensation, mild-to-moderate vision loss. For moderate- and high-dose regimens, corticosteroid eye drops must be given throughout cytarabine treatment and up to 72 hours posttreatment
    • Pulmonary toxicities: pulmonary edema, pneumonia
Fluoropyrimidines (5-Fluorouracil [5-FU] and prodrugs capecitabine and tegafur)


  • Gastrointestinal cancers
  • Breast
  • Ovarian
Fluoropyrimidines are analogs of uracil and thymine and inhibit both RNA and DNA (major mechanism) synthesis. Fluorodeoxyuridine monophosphate (FdUMP), the active metabolite of the prototype 5-FU binds to thymidylate synthase (TS), which normally catalyzes the conversion of dUMP to deoxythymidine monophosphate (dTMP). The resultant fluorodeoxythymidine monophosphate (FdTMP) is triphosphorylated and incorporated into DNA, subsequently causing single=strand breaks and termination of DNA replication.
The binding of FdUMP is stabilized by leucovorin, the reduced from of folate. See Chapter 4, Antimetabolites: Antifolates, for further discussion of folic acid metabolism and its role in the conversion of dUMP to dTMP.
  • Administered IV or orally
  • Renal excretion, requiring dose modification in the presence of reduced glomerular filtration rates
  • Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU; patients with a DPD deficiency are at risk of developing severe 5-FU-associated toxicity
  • Adverse events include:
    • Myelosuppression
    • GI toxicities (nausea, anorexia, vomiting, diarrhea, oral mucositis)
    • Hepatotoxicity
    • Cardiotoxicity (coronary vasospasm, QT prolongation)
    • Cerebellar toxicity
Gemcitabine

  • Monotherapy in pancreatic cancer
  • + Paclitaxel in breast cancer
  • + Carboplatin in ovarian cancer
  • + Cisplatin in NSCLC
  • + Cisplatin in bladder cancer
  • Cervical
  • Head and neck
  • Hepatobiliary
  • Refractory Hodgkin lymphoma
  • Sarcoma
  • Testicular germ cell tumor
Gemcitabine mimics cytosine and is transported into cells and phosphorylated to its triphosphate form to inhibit DNA synthesis by acting as a competitive inhibitor of DNA polymerase and by inhibition of RNR (targets M1 subunit)
Is usually given at 1,000 mg/m2 IV over 30 minutes
Is activated intracellularly by deoxycytidine kinase (DCK); may be given at fixed dose rate (FDR), e.g., 10 mg/m2/min to avoid DCK saturation
  • Intravenous (IV) administration. Can also be administered via intravesical instillation
  • Adverse events include:
    • myelosuppression (mainly neutropenia)
    • edema
    • fever
    • hepatotoxicity (primarily elevated transaminases but can elevate bilirubin too)
    • flu-like syndrome, including chills, cough, headache, rhinitis, myalgia, and fatigue
    • erythematous pruritic maculopapular rash
  • Rare adverse event: pneumonitis, hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP)

AML, acute myeloid leukemia; CNS, central nervous system; NHL, Non-Hodgkin lymphoma; NSCLC, non-small cell lung cancer.