Total marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil.

2.50
Hdl Handle:
http://hdl.handle.net/10541/96082
Title:
Total marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil.
Authors:
Molineux, Graham; Migdalska, A; Haley, John D; Evans, Gareth S; Dexter, T Michael
Abstract:
To examine the potential role of stem-cell factor (SCF) in cancer chemotherapy, we have administered it to mice either before or after 5-fluorouracil (5-FU). When polyethylene glycolated (PEG-ylated) SCF was administered to mice before 5-FU, it had a significant sensitizing effect on primitive bone marrow cells. Examination of the hematopoietic status of these mice showed that the damage caused by 5-FU to both bone marrow and spleen hematopoiesis was exaggerated when it was preceded by SCF. SCF given before each of two 5-FU treatments at 7-day intervals resulted in the death of all treated mice. The time of death and hematopoietic status of these animals are compatible with the onset of hypoplastic marrow failure leading to pancytopenia and death. SCF given after 5-FU had little impact either on the initial degree of hematopoietic damage or subsequent recovery. Gut populations were similarly sensitized to 5-FU by prior treatment with SCF, and the damage caused to intestinal populations was greater than that resulting from 5-FU alone. This indicates that the different tissues may be similarly sensitized by SCF. The sensitizing effect of SCF was reversed by concurrent administration of transforming growth factor (TGF)-beta 3, and survival of the majority of the mice was ensured. Examination of hematopoiesis in mice treated concurrently with SCF and TGF-beta 3 showed that the degree of marrow and spleen damage had reverted to that caused by 5-FU alone. In further experiments, 100% survival and normal hematopoiesis could be attained by transplantation of 1 million syngeneic bone marrow cells 24 hours after 5-FU treatment following SCF sensitization. These data indicate that PEG-ylated SCF can sensitize normally resistant hematopoietic and gut stem cells to the effects of 5-FU. This sensitization resulted in effective eradication of hematopoiesis in SCF-pretreated/5-FU-treated animals and their subsequent death from marrow failure. These findings imply that SCF pretreatment may represent a novel method of increasing the effectiveness of conventional chemotherapy, making marrow ablation more effective without drug dose escalation and perhaps sensitizing some tumor cells to the effects of therapy.
Affiliation:
Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital, Withington, UK.
Citation:
Total marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil. 1994, 83 (12):3491-9 Blood
Journal:
Blood
Issue Date:
15-Jun-1994
URI:
http://hdl.handle.net/10541/96082
PubMed ID:
7515714
Type:
Article
Language:
en
ISSN:
0006-4971
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorMolineux, Grahamen
dc.contributor.authorMigdalska, Aen
dc.contributor.authorHaley, John Den
dc.contributor.authorEvans, Gareth Sen
dc.contributor.authorDexter, T Michaelen
dc.date.accessioned2010-04-09T09:00:23Z-
dc.date.available2010-04-09T09:00:23Z-
dc.date.issued1994-06-15-
dc.identifier.citationTotal marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil. 1994, 83 (12):3491-9 Blooden
dc.identifier.issn0006-4971-
dc.identifier.pmid7515714-
dc.identifier.urihttp://hdl.handle.net/10541/96082-
dc.description.abstractTo examine the potential role of stem-cell factor (SCF) in cancer chemotherapy, we have administered it to mice either before or after 5-fluorouracil (5-FU). When polyethylene glycolated (PEG-ylated) SCF was administered to mice before 5-FU, it had a significant sensitizing effect on primitive bone marrow cells. Examination of the hematopoietic status of these mice showed that the damage caused by 5-FU to both bone marrow and spleen hematopoiesis was exaggerated when it was preceded by SCF. SCF given before each of two 5-FU treatments at 7-day intervals resulted in the death of all treated mice. The time of death and hematopoietic status of these animals are compatible with the onset of hypoplastic marrow failure leading to pancytopenia and death. SCF given after 5-FU had little impact either on the initial degree of hematopoietic damage or subsequent recovery. Gut populations were similarly sensitized to 5-FU by prior treatment with SCF, and the damage caused to intestinal populations was greater than that resulting from 5-FU alone. This indicates that the different tissues may be similarly sensitized by SCF. The sensitizing effect of SCF was reversed by concurrent administration of transforming growth factor (TGF)-beta 3, and survival of the majority of the mice was ensured. Examination of hematopoiesis in mice treated concurrently with SCF and TGF-beta 3 showed that the degree of marrow and spleen damage had reverted to that caused by 5-FU alone. In further experiments, 100% survival and normal hematopoiesis could be attained by transplantation of 1 million syngeneic bone marrow cells 24 hours after 5-FU treatment following SCF sensitization. These data indicate that PEG-ylated SCF can sensitize normally resistant hematopoietic and gut stem cells to the effects of 5-FU. This sensitization resulted in effective eradication of hematopoiesis in SCF-pretreated/5-FU-treated animals and their subsequent death from marrow failure. These findings imply that SCF pretreatment may represent a novel method of increasing the effectiveness of conventional chemotherapy, making marrow ablation more effective without drug dose escalation and perhaps sensitizing some tumor cells to the effects of therapy.en
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subjectHaematopoietic Cell Growth Factorsen
dc.subject.meshAnimals-
dc.subject.meshBone Marrow-
dc.subject.meshBone Marrow Transplantation-
dc.subject.meshFemale-
dc.subject.meshFluorouracil-
dc.subject.meshGranulocyte Colony-Stimulating Factor-
dc.subject.meshHematopoietic Cell Growth Factors-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshMice-
dc.subject.meshMice, Inbred Strains-
dc.subject.meshPolyethylene Glycols-
dc.subject.meshStem Cell Factor-
dc.subject.meshTransforming Growth Factor beta-
dc.titleTotal marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil.en
dc.typeArticleen
dc.contributor.departmentDepartment of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital, Withington, UK.en
dc.identifier.journalBlooden
All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.