9-arabinofuranosylguanine and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

GW506U78 or nelarabine (Glaxo-SmithKline) is a nucleoside analog that is rapidly converted by cells of lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate (araGTP). The triphosphate form of araG acts as a substrate for DNA polymerases and araG gets incorporated into the DNA, resulting in inhibition of DNA synthesis and subsequent cytotoxicity. It has been shown that nelarabine has activity as a single agent in patients with T-cell malignancies that have relapsed or are refractory to other therapy. The ongoing research on nelarabine has earned fast-track status from the U.S. Food and Drug Administration (FDA) for treatment of patients with T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma who have not responded to or whose disease has progressed during treatment with at least two standard regimens. It is likely that nelarabine will be a useful drug in the treatment of leukemic diseases in the future and therefore nelarabine is an interesting drug to study further. Here we present an overview of what is known about the mechanism of action of nelarabine and its status in clinical trials.

Topics: Arabinonucleosides; Clinical Trials as Topic; DNA Repair; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Hematologic Neoplasms; Humans; Leukemia-Lymphoma, Adult T-Cell; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome; Vidarabine

Arabinosylguanine (araG) is a nucleoside analog that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate, resulting in inhibition of DNA synthesis and selective in vitro toxicity to T lymphoblastoid cell lines as well as to freshly isolated leukemia cells from patients with T cell acute lymphoblastic leukemia. In this report, we demonstrate that araG is an effective agent to use for chemoseparation of malignant T lymphoblasts from human bone marrow. When freshly isolated human T leukemia cells or T lymphoblastoid cells were treated with 100 microM araG for 18 hr, up to 6 logs of clonogenic T cells could be eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We discuss the use of this agent in ex vivo elimination of residual malignant T cells from marrow of patients requiring myeloablative chemotherapy with autologous bone marrow rescue.

Topics: Antineoplastic Agents; Arabinonucleosides; Arabinonucleotides; Bone Marrow Purging; Cell Death; Cell Division; Cell Separation; Clone Cells; Erythroid Precursor Cells; Guanosine Triphosphate; Humans; Leukemia-Lymphoma, Adult T-Cell; Pentostatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Tumor Cells, Cultured