Guanine arabinoside as a bone marrow-purging agent.
Arabinosylguanine (araG) is a nucleoside analogue that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate (araGTP), 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 (ALL). We have previously demonstrated 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 hours, up to 6 logs of clonogenic T cells are eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We subsequently described studies in a murine model of T cell acute lymphoblastic leukemia (ALL) in which we tested whether bone marrow contaminated with malignant T cells and purged ex vivo with araG, could reconstitute both the lymphoid and myeloerythroid lineages in the absence of leukemic relapse. The model utilized 6C3HED tumor cells, derived from a Thy 1.2+ malignant murine T cell line, which were shown to cause lethal leukemia in C3H/HeN mice. Intravenous injection of 10(6) 6C3HED cells resulted in 100 percent mortality within 18 days, with autopsy revealing tumor infiltration of multiple organs. Evidence of araG's ability to purge bone marrow of malignant tumor cells without causing significant toxicity to normal marrow-derived hematopoietic progenitor cells was documented in experiments in which 75 percent of lethally irradiated mice receiving transplants of syngeneic bone marrow contaminated with 6C3HED tumor cells and treated ex vivo with 100 mM araG for 18 hours survived for 250 to > 400 days. Reconstitution of the lymphoid, myeloid, and erythroid lineages with donor cells in surviving mice was documented. The data presented indicate that araG may effectively purge bone marrow of malignant T cells without irreversible toxicity to hematopoietic stem cells. This purging regimen is recommended for consideration for clinical trials in patients with T cell malignancies undergoing autologous bone marrow transplantation and may also be a viable option for T cell depletion as a strategy to prevent graft versus host disease.
Kurtzberg
J
J
Pediatric Bone Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina 27710.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001088:Arabinonucleotides / Q000378:metabolism; D016465:Bone Marrow Purging; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D013601:T-Lymphocytes / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D001088:Arabinonucleotides; C028771:9-arabinofuranosylguanine; C022206:9-beta-D-arabinofuranosylguanosine 5'-triphosphate; D006160:Guanosine Triphosphate