Gravatt L C, Chaffee S, Hebert M E, Halperin E C, Friedman H S, Kurtzberg J
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710.
Leukemia. 1993 Aug;7(8):1261-7.
9-beta-D-Arabinofuranosylguanine (araG), an analog of deoxyguanosine which is not degraded by purine nucleoside phosphorylase, has been previously shown in in vitro studies by our laboratory to be effective in purging malignant T cells from human bone marrow (1). We now describe 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% mortality within 18 days, with autopsy revealing tumor infiltration of multiple organs. 100% of non-leukemia bearing lethally irradiated C3H/HeN mice transplanted with syngeneic bone marrow, treated ex vivo with 100 microM of araG for 18 hours, survived > 365 days post-transplant with full lymphohematopoietic reconstitution. 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% of lethally irradiated mice transplanted with syngeneic bone marrow, contaminated with 6C3HED tumor cells and treated ex vivo with 100 microM araG for 18 hours, survived for > 250 to > 400 days. Death in 25% of mice was secondary to infection which developed before marrow reconstitution occurred. 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.
9-β-D-阿拉伯呋喃糖基鸟嘌呤（araG）是脱氧鸟苷的类似物，不会被嘌呤核苷磷酸化酶降解。此前，我们实验室的体外研究表明，它在清除人骨髓中的恶性T细胞方面有效（1）。我们现在描述在T细胞急性淋巴细胞白血病（ALL）小鼠模型中的研究，在该模型中，我们测试了被恶性T细胞污染并在体外经araG清除的骨髓，能否在无白血病复发的情况下重建淋巴系和髓系红细胞系。该模型使用源自Thy 1.2+恶性小鼠T细胞系的6C3HED肿瘤细胞，已证明其可在C3H/HeN小鼠中引发致命性白血病。静脉注射10(6)个6C3HED细胞会导致18天内100%死亡，尸检显示多个器官有肿瘤浸润。100%接受同基因骨髓移植的非白血病致死性照射C3H/HeN小鼠，在体外经100微摩尔araG处理18小时后，移植后存活超过365天，实现了完全的淋巴细胞造血重建。在实验中记录了araG清除骨髓中恶性肿瘤细胞而不对正常骨髓来源的造血祖细胞造成显著毒性的证据，在这些实验中，75%接受同基因骨髓移植的致死性照射小鼠，骨髓被6C3HED肿瘤细胞污染并在体外经100微摩尔araG处理18小时，存活超过250至超过400天。25%的小鼠死亡继发于骨髓重建前发生的感染。记录了存活小鼠中供体细胞对淋巴系、髓系和红细胞系的重建情况。所呈现的数据表明，araG可有效清除骨髓中的恶性T细胞，而对造血干细胞无不可逆毒性。建议将这种清除方案考虑用于接受自体骨髓移植的T细胞恶性肿瘤患者的临床试验，并且作为预防移植物抗宿主病的策略，它也可能是T细胞去除的可行选择。
