Chemotherapy

 

 

Antimetabolites

Most agents are cell cycle specific

  • S phase

Antimetabolities masquerade as the normal cellular metabolites that are required for cell function and replication.

Interfere directly with normal cell metabolism, interacting directly with specific enzymes by either inhibiting production of the enzyme or by producing a nonfunctional end product.

Cell processes dependent upon that enzyme or the end product are thus blocked, inhibiting protein, RNA or DNA synthesis.

Major toxicities:

  • Bone Marrow Suppression
  • Nausea, vomiting, anorexia
  • Hepatotoxic

 

Examples:

FOLIC ACID ANTAGONISTS

Methotrexate

Trimetrexate

PYRIMIDINE ANTAGONISTS

Cytarabine (Cytosine arabinoside, ara-c) Gemcitabine

Fluorouracil (5-FU)

Azacytidine

 

 

PURINE ANTAGONISTS

Mercaptopurine (6-MP)

Thioguanine (6-TG)

Fludarabine

Cladribine

Clofarabine

Nelarabine

Fazarabine

 

Folic Acid Antagonists

Methotrexate

  • Used in ALL, lymphoma, osteosarcoma
  • Administered orally, intramuscular, intravenous or intrathecal
  • Leucovorin is administered as a rescue agent following high-dose therapy

 

Pyrimidine Antagonists

Cytarabine (ara-C)

  • Used in leukemia, lymphoma
  • Administered subcutaneously, intravenous or intrathecal
  • leukopenia  and  neutropenia onset within 24 hours, 1st nadir at 7-9 days with a brief recovery day 12, 2nd nadir greater than the first, at 15-24 days, recovery in the following 10 days

Gemcitabine

  • Used in relapsed or refractory leukemia, Hodgkin’s Disease
  • Prolonged administration, longer than 1 hour, has shown to increase toxicity

Fluoroucil

  • Used in hepatoblastoma, melanoma, and other malignancies in adults
  • May be used in combination with leucovorin to potentiate the anti-tumour activity of fluorooucil
  • Oral doses should be taken on an empty stomach (no food for 2 hours before and after)

 

Purine antagonists

 Mercaptopurine

  • Oral tablets used in leukemia and non-hodgkin’s lymphoma
  • Daily dose to be taken preferably at bedtime on an empty stomach, without milk products

Thioguanine

  • Oral tablets used in leukemia
  • Dose should be taken on an empty stomach to increase absorption, without milk products

Fludarabine

  • Primarily used as a conditioning regimen for allogeneic BMT

Cladribine

  • Newer agent used to treat relapsed or refractory leukemia
  • Cladribine has cytotoxic effects on actively dividing and resting cells

Clofarabine

  • Newer agent used to treat recurrent and refractory leukemia
  • Toxicity profile extensive: cardio-respiratory, CNS, dermatologic, GI, GU, bone marrow, liver.

Nelarabine

  • Used as front line, relapse or refractory therapy for T-cell leukemia, t-cell lymphoma
  • Toxicity profile extensive: cardio-respiratory, CNS, dermatologic, GI, bone marrow, liver, neuromuscular and skeletal

 

Side Effects and Toxicities

Side Effects and Toxicities common to most of the antimetabolites include:

  • Myelosuppression
  • Stomatitis
  • Nausea, vomiting, diarrhea (dose dependent)
  • Liver toxic

 

Antimetabolites most commonly used in pediatrics:

Drug

Side Effect/Toxicity

Special considerations

Methotrexate

Mucositis and GI ulceration can be severe with high doses

 

Photosensitivity, rash

 

IT administration associated with CNS toxicity

 

Nephrotoxic

 

  • Leucovorin “rescues” normal cells from cytotoxic effects
  • Timing of leucovorin is crucial!
  • Hydration and urine alkalinization with high dose infusions to prevent crystallization in the kidneys

Cytaribine

Conjunctivitis with high doses

 

IT administration associated with CNS toxicity, immediate nausea and vomiting

 

Flu-like syndrome, fever

  • Use of prophylactic steroid eye drops is indicated with high dose
  • Pre-medicate with antiemetics prior to administration

Mercaptopurine

Dose limiting side effect: myelosuppression

  • Dose may need to be reduced during maintenance phase for myleosuppression
  • Reduce oral dose by 75% if given with allopurinol

Thioguanine

Delayed nadir

  • Cross-resistance with mercaptopurine

 

 

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