DRUG STUDY AND INFORMATION FORM Generic Name: Cytarabine (Cytosine Arabinoside; Ara-C) Trade Name: Cytosar-U, Tarabine

PFS Drug Class: Pyrimidine Analogs (Cytidine Analog) Structure/Chemistry: Analog of 2-deoxycytidine

Pharmacodynamics

Mechanism of Action: Ara-C contains a 2-hydroxyl that is trans to the 3-hydroxyl of the sugar. The 2-hydroxyl hinders rotation of the base around the nucleoside bond and interferes with base pairing. Ara-C is enters cells through a nucleoside transporter (hENT1, highly expressed in patients with AML and MLL) and then is converted to its active form (5monophosphate ribonucleotide [Ara-CMP]) by deoxycytidine kinase (exhibits polymorphic expression among patients)

Pharmacologic Effects: Ara-C is a potent inhibitor of DNA polymerase, both in DNA synthesis and repair, and blocks the further elongation of the nascent DNA molecule. Checkpoint kinases attempt to repair the offending nucleotide; if unable, DNA strand breaks occur, and apoptosis ensues. The drug must continually inhibit DNA synthesis for a duration of one cell cycle (24 hours) to expose most tumor cells during the S phase of the cycle. Optimal interval for IV bolus doses is between 8 and 12 hours.

Drug Resistance or Tolerance: Primary mechanism of resistance due to loss of activating enzyme deoxycytidine kinase. Enzymatic degradation by cytidine deaminase (Ara-CAra-U) has low activity in AML cells; also by dCMP deaminase (Ara-CMPAra-UMP).

Pharmacokinetics

Absorption: Poor oral bioavailability; must be given IV either rapidly every 12 hours or continuously every 5-7 days. Children tolerate higher doses better than adults. Distribution:

Elimination: t1/2 of 10 mins in plasma.

Metabolism: Most of the drug is rapidly deaminated to Ara-U

Adverse Side Effects/Toxicity: Myelosuppression (leukopenia, thrombocytopenia, and anemia), GI disturbances, stomatitis, conjunctivitis, reversible hepatic enzyme elevations, noncardiogenic pulmonary edema, and dermatitis. Following high doses, an onset of dyspnea, fever, and pulmonary infiltrates may prove fatal. Cerebellar and cerebral toxicity may follow intrathecal administration Drug Interactions:

Therapeutic uses: The most important antimetabolite used to treat AML (acute myelogenous leukemia). Also can treat ALL (acute lymphoblastic leukemia), CML (chronic myelogenous leukemia), acute promyelocytic leukemia, and high-grade lymphomas

Miscellaneous: Either intrathecal administration of cytarabine every four hours for treatment of meningeal or lymphomatous leukemia in the CSF or give depot liposomal formulation (Depocyt) which provides sustained release into the CSF