Targeting myeloid leukemia with a DT390-mIL-3 fusion immunotoxin: ex vivo and in vivo studies in mice |
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Authors: | Vallera Daniel A; Seo Su-Yeong; Panoskaltsis-Mortari Angela; Griffin James D; Blazar Bruce R |
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Affiliation: | University of Minnesota Cancer Center,
1 Departments of Therapeutic Radiology (Section on Experimental Cancer Immunology) and
4 Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN 55455, USA,
3 Department of Microbiology, College of Medicine,Dong-A University, Pusan, South Korea and
5 Dana-Farber Cancer Institute, Boston, MA, USA |
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Abstract: | The IL-3 receptor was expressed on a high frequency of myeloidleukemia cells and also on hematopoietic and vascular cells.We previously showed that a recombinant IL-3 fusion immunotoxin(DT390IL-3) expressed by splicing the murine IL-3 gene to atruncated diphtheria toxin (DT390) gene selectively killed IL-3R+expressing cells and was not uniformly toxic to uncommited BMprogenitor cells (Chan,C.-H., Blazar,B.R., Greenfield,L., Kreitman,R.J.and Vallera,D.A., 1996, Blood, 88, 14451456). Thus, weexplored the feasability of using DT390IL-3 as an anti-leukemiaagent. DT390IL-3 was toxic when administered to mice at dosesas low as 0.1 µg/day. The dose limiting toxicity appearedto be related to platelet and bleeding effects of the fusiontoxin. Because of these effects, DT390IL-3 was studied ex vivoas a means of purging contaminating leukemia cells from BM graftsin a murine autologous BM transplantation. In this setting,as few as 1000 IL-3R-expressing, bcr/abl transformed myeloid32Dp210 leukemia cells were lethal. An optimal purging intervalof 10 nM/l for 8 h eliminated leukemia cells from 32Dp210/BMmixtures given to lethally irradiated (8 Gy) C3H/HeJ syngeneicmice. Mice given treated grafts containing BM and a lethal doseof 32Dp210 cells survived over 100 days while mice given untreatedgrafts did not survive (P < 0.00001). DT390IL-3 may provehighly useful for ex vivo purging of lethal malignant leukemiacells from autologous BM grafts. |
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Keywords: | bone marrow transplantation/ cancer/ diphtheria toxin/ IL-3/ immunotoxin |
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