Variable cytotoxicity of diphtheria toxin 388-granulocyte-macrophage colony-stimulating factor fusion protein for acute myelogenous leukemia stem cells

Citation
M. Feuring-buske et al., Variable cytotoxicity of diphtheria toxin 388-granulocyte-macrophage colony-stimulating factor fusion protein for acute myelogenous leukemia stem cells, EXP HEMATOL, 28(12), 2000, pp. 1390-1400
Citations number
48
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
EXPERIMENTAL HEMATOLOGY
ISSN journal
0301472X → ACNP
Volume
28
Issue
12
Year of publication
2000
Pages
1390 - 1400
Database
ISI
SICI code
0301-472X(200012)28:12<1390:VCODT3>2.0.ZU;2-L
Abstract
Objective. In this study, the utility of DT388-granulocyte-macrophage colon y-stimulating factor (GM-CSF) for the ex vivo purging and direct administra tion to patients with acute myeloid leukemia (AML) is tested using clonogen ic assays, long-term cultures (LTC), and NOD/SCID mice as assays for leukem ic progenitors. Materials and Methods. We compare the ability of 24-hour exposure to 0.3 mu g/mL (4 nM) DT388-GM-CSF to kill AML colony forming cells (CFC) and the mor e primitive AML progenitors detected after 6 weeks in stromal cocultures (A ML LTC-initiating cells or AML LTC-IC) and after 8 weeks in NOD/SCID mice. Results. AML samples (n = 10), expressing a mean of 35 to 1466 GM-CSF recep tors/blast, showed mean (range) percent kills of AML CFC and LTC-IC of 61 ( 17-98) and 46 (0-94) respectively with a direct correlation (r = 0.69) betw een the % kills detected in the in vitro assays. Among 5 evaluable samples the percent reduction in AML cell engraftment in NODI SCID marrow following ex vivo DT388-GM-CSF treatment varied from 38% to 100%. 40% to 56% of norm al bone marrow CFC and 31% to 45% of normal ETC-IC survived the same ex viv o treatment (n = 3). In subsequent experiments, NOD/SCID mice received AML blast cell injections intravenously followed in 24 hours by 1.5 mug DT388-G M-CSF daily intraperitoneally for 5 days. A reduction of marrow blast cells was seen with 7 of 9 samples tested 4 to 12 weeks post one course of toxin . Repeating the 5-day course of toxin 2 or 3 times at 4-week intervals did not improve the response, while delaying administration until 4 to 8 weeks post AML cell injection reduced the toxin's effectiveness (n = 5). Conclusion. This fusion toxin may prove useful for in vitro purging of stem cell harvests from selected AML patients and far direct administration to such patients. (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc.