Antimetabolites Flashcards
Methotrexate
Class: Folate analog
Mechanism of action: Inhibits the enzyme dihydrofolate reductase which normally converts dietary folate to tetrahydrofolate form which is required for thymidine and purine biosynthesis.
Therapeutic uses: Childhood ALL and choriocarcinoma, Burkitt’s lymphoma, breast, ovary, head and neck, bladder if given orally
If given intrathecally can be used to treat meningeal leukemia and meningeal metastases
High doses may be used for osteosarcomas
Toxicity: spontaneous hemorrhage and myelosuppresion of bone marrow, oral ulceration, stomatitis, renal toxicity (crystallizes in the urine and causes renal damage), hepatoxicity (fibrosis, cirrhosis), reproductive toxicity (defective oogenesis/spermatogenesis, abortion)
Other: Give Leucovorin to prevent toxic effects in normal cells but not tumor cells.
Pemetrexed
Class: Folate analog
Mechanism of action: Metabolized to polyglutamate form which inhibits several THF enzymes such as dihydrofolate reductase and thymidylate synthase.
Therapeutic uses: colon cancer, mesothelioma, non-small cell lung cancer, pancreatic cancer
Toxicity: No SEs.
5-Fluorouracil
Class: Pyrimidine analog
Mechanism of action: 5-Fluorouracil is a pro-drug that metabolized into both 5-FdUMP and 5-FdUTP. 5-FdUMP inhibits thymidylate synthetase preventing the synthesis of thymidine and 5-FdUTP is incorporated into RNA by RNA polymerase and interferes with RNA function.
Therapeutic uses: Breast, colorectal, gastric, head and neck, pancreatic by IV (toxic to GI tract, rapidly metabolized and cleared)
Topically for BCC
Toxicity: Hand-foot syndrome (erythema, sensitivity of palms and soles can occur)
Cardiac toxicity (acute chest pain)
anorexia, mucosal ulcerations, stomatitis, diarrhea
myelosuppression (anemia, thrombocytopenia).
Other: Can give Leucovorin to protect from side effects
Cytarabine (Ara-C)
Class: Pyrimidine analog
Mechanism of action: Ara-C is converted to Ara-CMP by deoxycytidine kinase. Ara-CMP is converted to Ara-CTP and placed on DNA strand during replication ending replication at that point.
Therapeutic uses: Most effective agent for acute myeloid leukemia (AML) but also works for ALL and blast phase CML.
Toxicity: Myelosuppression and GI toxicity (oral ulceration, stomatitis diarrhea)
Gemcitabine (dFdC)
Class: Pyrimidine analog
Mechanism of action: dFdC is converted to active metabolites dFdCDP and dFdCTP. dFdCDP inhibits ribonucleotide reductase resulting in depletion of deoxyribonucleotide pools necessary for DNA synthesis. dFdCTP incorporates into DNA and leads to termination and DNA synthesis.
Therapeutic uses: First line treatment for pancreatic
Also used for non-small cell lung, ovarian bladder, esophageal, and head and neck
Toxicity: Myelosuppression and flu-like syndrome
Other: More effective against solid tumors than cytarabine.
6-Mercaptopurine
Class: Purine analog
Mechanism of action: 6-Mercaptopurine is a prodrug that is converted to TIMP by HGPRT. TIMP inhibits the first step of purine synthesis as well as blocks the formation of AMP and xanthinylic acid from inosinic acid. TIMP may also be converted to thio-guanine ribonucleotides which are incorporated into DNA and RNA resulting in inhibition of DNA and RNA synthesis.
Therapeutic uses: Maintain remission in patients with ALL.
Toxicity: Bone Marrow suppression, hepatotoxicity in prolonged use
Other: Allopurinol which is often given to people on chemo will inhibit xanthine oxidase and allow for 6-Mercaptopurine to accumulate to higher levels at same dose; therefore you will need to give lower doses to patients on allopurinol.
