Description

Cancer

Description

Nelarabine (Arranon, 506U78) is a purine nucleoside analog and DNA synthesis inhibitor for HSB2 cell lines and ALL-SIL cell lines with IC50 of 0.13 μg/mL and 0.37 μg/mL, respectively.

Targets

IC₅₀

In Vitro

The IC50 of Nelarabine is 25-fold and 113-fold higher than ARAC in T- and B-lineage, respectively. T-ALL cells are eightfold more sensitive to Nelarabine than B-lineage but there is considerable overlap. The efficacy of NEL in T-lineage and B-lineage cell lines is 25-fold and 113-fold less than ARAC, respectively. ^[1] Nelarabine acts by inhibiting DNA synthesis and inducing apoptosis in susceptible cells. ^[2]Nelarabine demonstrated significant antineoplastic activity with acceptable toxicity. ^[3]

In Vivo

The Nelarabine plasma AUC is 2.82 mM minutes and the ara-G plasma AUC is 20 mM minutes. The terminal half-life of Nelarabine in plasma is 25 min, clearance is 42 mL/minutes/kg, and central volume of distribution is 1.1 L/kg. The terminal half-life of ara-G in plasma is 182 minutes and the central volume of distribution is 1.4 L/kg. In CSF the terminal half-life of Nelarabine is 77 minutes and of ara-G is 232 minutes. The AUCcsf:AUCplasma is 29 % for Nelarabine and 23 % for ara-G. Nelarabine and ara-G do not accumulate with daily infusions because of their relatively short half-lives. ^[4]

Clinical Trials

Nelarabine plus Doxorubicin, Cyclophosphamide,Cytarabine, Dexamethasone, Methotrexate or Vincristine has entered in a phase II clinical trial in the treatment of leukemia, acute lymphoblastic leukemia, and lymphoblastic lymphoma.

Features

Nelarabine is rapidly converted into ara-G through demethoxylation by adenosine deaminase.

Cell Lines

HSB2, ALL-SIL, JURKAT and PER-255 cell lines

Concentrations

0.125 μg/mL - 8 μg/mL

Incubation Time

96 hours

Methods

HSB2, ALL-SIL, JURKAT and PER-255 cell lines are tested for drug resistance using the MTT assay. Nelarabine are incubated over 4 days, with concentration tested in triplicate. The IC50 (drug concentration that inhibits cell growth by 50%) is used as the measure of drug resistance. Data represent the average of 2–6 experiments performed on separate occasions. In cases where 50% cytotoxicity is not achieved by even the highest dose in a particular experiment, the IC50 is recorded as double the highest concentration tested.

Animal Models

Healthy adult male rhesus monkeys

Formulation

Control

Doses

35 mg/kg

Administration

Administered via i.v.