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
|
|
Cytaribine |
Conjunctivitis with high doses
IT administration associated with CNS toxicity, immediate nausea and vomiting
Flu-like syndrome, fever |
|
Mercaptopurine |
Dose limiting side effect: myelosuppression |
|
Thioguanine |
Delayed nadir |
|
