Recombinant transforming growth factor β1 and β2 protect mice from acutely lethal doses of 5-fluorouracil and doxorubicin

Krzysztof Grzegorzewski, Francis W. Ruscetti, Noriko Usui, Giovanna Damia, Dan L. Longo, Joseph A. Carlino, Jonathan R. Keller, Robert H. Wiltrout

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Abstract

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.

Original languageEnglish
Pages (from-to)1047-1057
Number of pages11
JournalJournal of Experimental Medicine
Volume180
Issue number3
DOIs
Publication statusPublished - Sep 1 1994

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ASJC Scopus subject areas

  • Immunology

Cite this

Grzegorzewski, K., Ruscetti, F. W., Usui, N., Damia, G., Longo, D. L., Carlino, J. A., Keller, J. R., & Wiltrout, R. H. (1994). Recombinant transforming growth factor β1 and β2 protect mice from acutely lethal doses of 5-fluorouracil and doxorubicin. Journal of Experimental Medicine, 180(3), 1047-1057. https://doi.org/10.1084/jem.180.3.1047