TY - JOUR
T1 - Recombinant transforming growth factor β1 and β2 protect mice from acutely lethal doses of 5-fluorouracil and doxorubicin
AU - Grzegorzewski, Krzysztof
AU - Ruscetti, Francis W.
AU - Usui, Noriko
AU - Damia, Giovanna
AU - Longo, Dan L.
AU - Carlino, Joseph A.
AU - Keller, Jonathan R.
AU - Wiltrout, Robert H.
PY - 1994/9/1
Y1 - 1994/9/1
N2 - Transforming growth factor β1 (TGF-β1) and TGF-β2 can reversibly inhibit the proliferation of hematopoietic progenitor cells in vivo, leading us to hypothesize that such quiescent progenitors might be more resistant to high doses of cell cycle active chemotherapeutic drugs, thereby allowing dose intensification of such agents. Initial studies showed that whereas administration of TGF-β1 or TGF-β2 did not prevent death in normal mice treated with high doses of 5-fluorouracil (5-FU), those mice that received TGF-β2 did exhibit the beginning of a hematologic recovery by day 11 after administration of 5-FU, and were preferentially rescued by a suboptimal number of transplanted bone marrow cells. Subsequently, it was found that the administration of TGF-β2 protected recovering progenitor cells from high concentrations of 5-FU in vitro. This protection coincided with the finding that significantly more progenitors for colony-forming unit-culture (CFU-c) and CFU-granulocyte, erythroid, megakaryocyte, macrophage (GEMM) were removed from S-phase by TGF-β in mice undergoing hematopoietic recovery than in normal mice. Further studies showed that the administration of TGF-β protected up to 90% of these mice undergoing hematologic recovery from a rechallenge in vivo with high dose 5-FU, while survival in mice not given TGF-β was 1 or TGF-β2 also protected 70-80% of mice from lethal doses of the noncycle active chemotherapeutic drug, doxorubicin hydrochloride (DXR). These results demonstrate that TGF-β can protect mice from both the lethal hematopoietic toxicity of 5-FU, as well as the nonhematopoietic toxicity of DXR. This report thus shows that a negative regulator of hematopoiesis can be successfully used systemically to mediate chemoprotection in vivo.
AB - Transforming growth factor β1 (TGF-β1) and TGF-β2 can reversibly inhibit the proliferation of hematopoietic progenitor cells in vivo, leading us to hypothesize that such quiescent progenitors might be more resistant to high doses of cell cycle active chemotherapeutic drugs, thereby allowing dose intensification of such agents. Initial studies showed that whereas administration of TGF-β1 or TGF-β2 did not prevent death in normal mice treated with high doses of 5-fluorouracil (5-FU), those mice that received TGF-β2 did exhibit the beginning of a hematologic recovery by day 11 after administration of 5-FU, and were preferentially rescued by a suboptimal number of transplanted bone marrow cells. Subsequently, it was found that the administration of TGF-β2 protected recovering progenitor cells from high concentrations of 5-FU in vitro. This protection coincided with the finding that significantly more progenitors for colony-forming unit-culture (CFU-c) and CFU-granulocyte, erythroid, megakaryocyte, macrophage (GEMM) were removed from S-phase by TGF-β in mice undergoing hematopoietic recovery than in normal mice. Further studies showed that the administration of TGF-β protected up to 90% of these mice undergoing hematologic recovery from a rechallenge in vivo with high dose 5-FU, while survival in mice not given TGF-β was 1 or TGF-β2 also protected 70-80% of mice from lethal doses of the noncycle active chemotherapeutic drug, doxorubicin hydrochloride (DXR). These results demonstrate that TGF-β can protect mice from both the lethal hematopoietic toxicity of 5-FU, as well as the nonhematopoietic toxicity of DXR. This report thus shows that a negative regulator of hematopoiesis can be successfully used systemically to mediate chemoprotection in vivo.
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U2 - 10.1084/jem.180.3.1047
DO - 10.1084/jem.180.3.1047
M3 - Article
C2 - 8064224
AN - SCOPUS:0028129539
VL - 180
SP - 1047
EP - 1057
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 3
ER -