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. 1994 Sep 1;180(3):1047–1057. doi: 10.1084/jem.180.3.1047

Recombinant transforming growth factor beta 1 and beta 2 protect mice from acutely lethal doses of 5-fluorouracil and doxorubicin

PMCID: PMC2191629  PMID: 8064224

Abstract

Transforming growth factor beta 1 (TGF-beta 1) and TGF-beta 2 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-beta 1 or TGF-beta 2 did not prevent death in normal mice treated with high doses of 5-fluorouracil (5-FU), those mice that received TGF-beta 2 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-beta 2 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-beta in mice undergoing hematopoietic recovery than in normal mice. Further studies showed that the administration of TGF-beta 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-beta was < 40%. Pretreatment of mice with TGF-beta 1 or TGF-beta 2 also protected 70-80% of mice from lethal doses of the noncycle active chemotherapeutic drug, doxorubicin hydrochloride (DXR). These results demonstrate that TGF-beta 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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Selected References

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  1. Acton E. M., Tong G. L., Mosher C. W., Wolgemuth R. L. Intensely potent morpholinyl anthracyclines. J Med Chem. 1984 May;27(5):638–645. doi: 10.1021/jm00371a014. [DOI] [PubMed] [Google Scholar]
  2. Alderton P. M., Gross J., Green M. D. Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model. Cancer Res. 1992 Jan 1;52(1):194–201. [PubMed] [Google Scholar]
  3. Anilkumar T. V., Sarraf C. E., Hunt T., Alison M. R. The nature of cytotoxic drug-induced cell death in murine intestinal crypts. Br J Cancer. 1992 Apr;65(4):552–558. doi: 10.1038/bjc.1992.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Belizario J. E., Dinarello C. A. Interleukin 1, interleukin 6, tumor necrosis factor, and transforming growth factor beta increase cell resistance to tumor necrosis factor cytotoxicity by growth arrest in the G1 phase of the cell cycle. Cancer Res. 1991 May 1;51(9):2379–2385. [PubMed] [Google Scholar]
  5. Bonewald L. F. Can transforming growth factor beta be useful as a protective agent for pluripotent hematopoietic progenitor cells? Exp Hematol. 1992 Dec;20(11):1249–1251. [PubMed] [Google Scholar]
  6. Bradley T. R., Hodgson G. S. Detection of primitive macrophage progenitor cells in mouse bone marrow. Blood. 1979 Dec;54(6):1446–1450. [PubMed] [Google Scholar]
  7. Broxmeyer H. E. Suppressor cytokines and regulation of myelopoiesis. Biology and possible clinical uses. Am J Pediatr Hematol Oncol. 1992 Spring;14(1):22–30. doi: 10.1097/00043426-199221000-00003. [DOI] [PubMed] [Google Scholar]
  8. Cashman J. D., Eaves A. C., Raines E. W., Ross R., Eaves C. J. Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. I. Stimulatory role of a variety of mesenchymal cell activators and inhibitory role of TGF-beta. Blood. 1990 Jan 1;75(1):96–101. [PubMed] [Google Scholar]
  9. Castelli M. P., Black P. L., Schneider M., Pennington R., Abe F., Talmadge J. E. Protective, restorative, and therapeutic properties of recombinant human IL-1 in rodent models. J Immunol. 1988 Jun 1;140(11):3830–3837. [PubMed] [Google Scholar]
  10. Damia G., Komschlies K. L., Futami H., Back T., Gruys M. E., Longo D. L., Keller J. R., Ruscetti F. W., Wiltrout R. H. Prevention of acute chemotherapy-induced death in mice by recombinant human interleukin 1: protection from hematological and nonhematological toxicities. Cancer Res. 1992 Aug 1;52(15):4082–4089. [PubMed] [Google Scholar]
  11. Ellingsworth L. R., Brennan J. E., Fok K., Rosen D. M., Bentz H., Piez K. A., Seyedin S. M. Antibodies to the N-terminal portion of cartilage-inducing factor A and transforming growth factor beta. Immunohistochemical localization and association with differentiating cells. J Biol Chem. 1986 Sep 15;261(26):12362–12367. [PubMed] [Google Scholar]
  12. Futami H., Jansen R., MacPhee M. J., Keller J., McCormick K., Longo D. L., Oppenheim J. J., Ruscetti F. W., Wiltrout R. H. Chemoprotective effects of recombinant human IL-1 alpha in cyclophosphamide-treated normal and tumor-bearing mice. Protection from acute toxicity, hematologic effects, development of late mortality, and enhanced therapeutic efficacy. J Immunol. 1990 Dec 15;145(12):4121–4130. [PubMed] [Google Scholar]
  13. Goey H., Keller J. R., Back T., Longo D. L., Ruscetti F. W., Wiltrout R. H. Inhibition of early murine hemopoietic progenitor cell proliferation after in vivo locoregional administration of transforming growth factor-beta 1. J Immunol. 1989 Aug 1;143(3):877–880. [PubMed] [Google Scholar]
  14. Graham G. J., Pragnell I. B. Negative regulators of haemopoiesis--current advances. Prog Growth Factor Res. 1990;2(3):181–192. doi: 10.1016/0955-2235(90)90004-4. [DOI] [PubMed] [Google Scholar]
  15. Griswold D. P., Jr, Trader M. W., Frei E., 3rd, Peters W. P., Wolpert M. K., Laster W. R., Jr Response of drug-sensitive and -resistant L1210 leukemias to high-dose chemotherapy. Cancer Res. 1987 May 1;47(9):2323–2327. [PubMed] [Google Scholar]
  16. Hampson J., Ponting I. L., Cook N., Vodinelich L., Redmond S., Roberts A. B., Dexter T. M. The effects of TGF beta on haemopoietic cells. Growth Factors. 1989;1(2):193–202. doi: 10.3109/08977198909029128. [DOI] [PubMed] [Google Scholar]
  17. Harrison D. E., Lerner C. P. Most primitive hematopoietic stem cells are stimulated to cycle rapidly after treatment with 5-fluorouracil. Blood. 1991 Sep 1;78(5):1237–1240. [PubMed] [Google Scholar]
  18. Hodgson G. S., Bradley T. R. Properties of haematopoietic stem cells surviving 5-fluorouracil treatment: evidence for a pre-CFU-S cell? Nature. 1979 Oct 4;281(5730):381–382. doi: 10.1038/281381a0. [DOI] [PubMed] [Google Scholar]
  19. Iscove N. N., Till J. E., McCulloch E. A. The proliferative states of mouse granulopoietic progenitor cells. Proc Soc Exp Biol Med. 1970 May;134(1):33–36. doi: 10.3181/00379727-134-34721. [DOI] [PubMed] [Google Scholar]
  20. Jacobsen S. E., Keller J. R., Ruscetti F. W., Kondaiah P., Roberts A. B., Falk L. A. Bidirectional effects of transforming growth factor beta (TGF-beta) on colony-stimulating factor-induced human myelopoiesis in vitro: differential effects of distinct TGF-beta isoforms. Blood. 1991 Nov 1;78(9):2239–2247. [PubMed] [Google Scholar]
  21. Jacobsen S. E., Ruscetti F. W., Roberts A. B., Keller J. R. TGF-beta is a bidirectional modulator of cytokine receptor expression on murine bone marrow cells. Differential effects of TGF-beta 1 and TGF-beta 3. J Immunol. 1993 Nov 1;151(9):4534–4544. [PubMed] [Google Scholar]
  22. Jansen R., Damia G., Usui N., Keller J., Futami H., Goey H., Back T. T., Longo D. L., Ruscetti F. W., Wiltrout R. H. Effects of recombinant transforming growth factor-beta 1 on hematologic recovery after treatment of mice with 5-fluorouracil. J Immunol. 1991 Nov 15;147(10):3342–3347. [PubMed] [Google Scholar]
  23. Keller J. R., Jacobsen S. E., Sill K. T., Ellingsworth L. R., Ruscetti F. W. Stimulation of granulopoiesis by transforming growth factor beta: synergy with granulocyte/macrophage-colony-stimulating factor. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7190–7194. doi: 10.1073/pnas.88.16.7190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Keller J. R., Mantel C., Sing G. K., Ellingsworth L. R., Ruscetti S. K., Ruscetti F. W. Transforming growth factor beta 1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines. J Exp Med. 1988 Aug 1;168(2):737–750. doi: 10.1084/jem.168.2.737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Keller J. R., Mcniece I. K., Sill K. T., Ellingsworth L. R., Quesenberry P. J., Sing G. K., Ruscetti F. W. Transforming growth factor beta directly regulates primitive murine hematopoietic cell proliferation. Blood. 1990 Feb 1;75(3):596–602. [PubMed] [Google Scholar]
  26. Keller J. R., Sing G. K., Ellingsworth L. R., Ruscetti F. W. Transforming growth factor beta: possible roles in the regulation of normal and leukemic hematopoietic cell growth. J Cell Biochem. 1989 Feb;39(2):175–184. doi: 10.1002/jcb.240390209. [DOI] [PubMed] [Google Scholar]
  27. Keller J. R., Sing G. K., Ellingsworth L. R., Ruscetti S. K., Ruscetti F. W. Two forms of transforming growth factor-beta are equally potent selective growth inhibitors of early murine hematopoiesis. Ann N Y Acad Sci. 1990;593:172–180. doi: 10.1111/j.1749-6632.1990.tb16109.x. [DOI] [PubMed] [Google Scholar]
  28. Lemoli R. M., Strife A., Clarkson B. D., Haley J. D., Gulati S. C. TGF-beta 3 protects normal human hematopoietic progenitor cells treated with 4-hydroperoxycyclophosphamide in vitro. Exp Hematol. 1992 Dec;20(11):1252–1256. [PubMed] [Google Scholar]
  29. Lerner C., Harrison D. E. 5-Fluorouracil spares hemopoietic stem cells responsible for long-term repopulation. Exp Hematol. 1990 Feb;18(2):114–118. [PubMed] [Google Scholar]
  30. Lyons R. M., Moses H. L. Transforming growth factors and the regulation of cell proliferation. Eur J Biochem. 1990 Feb 14;187(3):467–473. doi: 10.1111/j.1432-1033.1990.tb15327.x. [DOI] [PubMed] [Google Scholar]
  31. Massagué J. The TGF-beta family of growth and differentiation factors. Cell. 1987 May 22;49(4):437–438. doi: 10.1016/0092-8674(87)90443-0. [DOI] [PubMed] [Google Scholar]
  32. Migdalska A., Molineux G., Demuynck H., Evans G. S., Ruscetti F., Dexter T. M. Growth inhibitory effects of transforming growth factor-beta 1 in vivo. Growth Factors. 1991;4(3):239–245. doi: 10.3109/08977199109104820. [DOI] [PubMed] [Google Scholar]
  33. Moore M. A. Review: Stratton Lecture 1990. Clinical implications of positive and negative hematopoietic stem cell regulators. Blood. 1991 Jul 1;78(1):1–19. [PubMed] [Google Scholar]
  34. Moore M. A., Stolfi R. L., Martin D. S. Hematologic effects of interleukin-1 beta, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in tumor-bearing mice treated with fluorouracil. J Natl Cancer Inst. 1990 Jun 20;82(12):1031–1037. doi: 10.1093/jnci/82.12.1031. [DOI] [PubMed] [Google Scholar]
  35. Moses H. L., Yang E. Y., Pietenpol J. A. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights. Cell. 1990 Oct 19;63(2):245–247. doi: 10.1016/0092-8674(90)90155-8. [DOI] [PubMed] [Google Scholar]
  36. Odom A. L., Hatwig C. A., Stanley J. S., Benson A. M. Biochemical determinants of Adriamycin toxicity in mouse liver, heart and intestine. Biochem Pharmacol. 1992 Feb 18;43(4):831–836. doi: 10.1016/0006-2952(92)90250-m. [DOI] [PubMed] [Google Scholar]
  37. Pizzo P. A. Granulocytopenia and cancer therapy. Past problems, current solutions, future challenges. Cancer. 1984 Dec 1;54(11 Suppl):2649–2661. doi: 10.1002/1097-0142(19841201)54:2+<2649::aid-cncr2820541409>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  38. Roberts A. B., Kim S. J., Kondaiah P., Jakowlew S. B., Denhez F., Glick A. B., Geiser A. G., Watanabe S., Noma T., Lechleider R. Transcriptional control of expression of the TGF-betas. Ann N Y Acad Sci. 1990;593:43–50. doi: 10.1111/j.1749-6632.1990.tb16098.x. [DOI] [PubMed] [Google Scholar]
  39. Sing G. K., Keller J. R., Ellingsworth L. R., Ruscetti F. W. Transforming growth factor beta selectively inhibits normal and leukemic human bone marrow cell growth in vitro. Blood. 1988 Nov;72(5):1504–1511. [PubMed] [Google Scholar]
  40. Smeland E. B., Blomhoff H. K., Holte H., Ruud E., Beiske K., Funderud S., Godal T., Ohlsson R. Transforming growth factor type beta (TGF beta) inhibits G1 to S transition, but not activation of human B lymphocytes. Exp Cell Res. 1987 Jul;171(1):213–222. doi: 10.1016/0014-4827(87)90264-3. [DOI] [PubMed] [Google Scholar]
  41. Sonis S. T., Lindquist L., Van Vugt A., Stewart A. A., Stam K., Qu G. Y., Iwata K. K., Haley J. D. Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta 3. Cancer Res. 1994 Mar 1;54(5):1135–1138. [PubMed] [Google Scholar]
  42. Spangrude G. J., Smith L., Uchida N., Ikuta K., Heimfeld S., Friedman J., Weissman I. L. Mouse hematopoietic stem cells. Blood. 1991 Sep 15;78(6):1395–1402. [PubMed] [Google Scholar]
  43. Van Zant G. Studies of hematopoietic stem cells spared by 5-fluorouracil. J Exp Med. 1984 Mar 1;159(3):679–690. doi: 10.1084/jem.159.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]

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