Total marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil.
AffiliationDepartment of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital, Withington, UK.
MetadataShow full item record
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.
CitationTotal marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil. 1994, 83 (12):3491-9 Blood
- Prophylactic pretreatment of mice with hematopoietic growth factors induces expansion of primitive cell compartments and results in protection against 5-fluorouracil-induced toxicity.
- Authors: de Haan G, Donte B, Engel C, Loeffler M, Nijhof W
- Issue date: 1996 Jun 1
- Stem cell factor has contrasting effects in combination with 5-fluorouracil or total-body irradiation on frequencies of different hemopoietic cell subsets and engraftment of transplanted bone marrow.
- Authors: Down JD, de Haan G, Dillingh JH, Dontje B, Nijhof W
- Issue date: 1997 Jun
- Contrasting mechanisms of the myeloprotective effects of interleukin-1 against ionizing radiation and cytotoxic 5-fluorouracil.
- Authors: Neta R, Keller JR, Ali N, Blanchette F, Dubois CM
- Issue date: 1996 May
- Bone marrow collected 14 days after in vivo administration of granulocyte colony-stimulating factor and stem cell factor to mice has 10-fold more repopulating ability than untreated bone marrow.
- Authors: Bodine DM, Seidel NE, Orlic D
- Issue date: 1996 Jul 1
- Possible role of stem cell factor as a serum factor: monoclonal anti-c-kit antibody abrogates interleukin-6-dependent colony growth in serum-containing culture.
- Authors: Shiohara M, Koike K, Kubo T, Amano Y, Takagi M, Muraoka K, Nakao J, Nakahata T, Komiyama A
- Issue date: 1993 Jul