Abstract
The haematopoietic system is sensitive to cytotoxic damage and is often the site of dose-limiting toxicity. We previously reported that swainsonine, an inhibitor of protein glycosylation, reduced the bone marrow toxicity resulting from a single dose of anticancer drugs in otherwise healthy mice. However, more important questions are (1) can swainsonine protect tumour-bearing mice without interfering with the anti-tumour effects of the drugs, and (2) can swainsonine stimulate haematopoietic activity of human, as well as murine, bone marrow. We demonstrate here that swainsonine protects C57BL/6 mice bearing melanoma-derived tumours from cyclophosphamide-induced toxicity without interfering with the drug’s ability to inhibit tumour growth. Similar results were obtained in vivo with 3´-azido-3´-deoxythymidine (AZT), a myelosuppressive agent often used in therapy for acquired immune deficiency syndrome. Swainsonine increased both total bone marrow cellularity and the number of circulating white blood cells in mice treated with doses of AZT that typically lead to severe myelosuppression. Swainsonine also increased the number of erythroid and myeloid colony forming cells (CFCs) in short-term cultures of murine bone marrow, restoring the number of progenitor cells to the control level in the presence of AZT doses that reduced CFCs by 80%. With respect to the sensitivity of human haematopoietic cells to swainsonine, we show that swainsonine protected human myeloid progenitor cells from AZT toxicity in vitro. These results suggest that swainsonine may be useful as an adjuvant in several types of human chemotherapy.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Abraham, N. G., Chertkov, J. L., Staudinger, R., Jiang, S., Lutton, J. D., Argani, I., Levere, R. D. & Kappas, A. (1993) Long-term bone marrow stromal and hemopoietic toxicity to AZT: protective role of heme and IL-1. Exp Hematol 21: 263–268.
Aidoudi, S., Guigon, M., Lebeurier, I., Caen, J. P. & Han, Z. C. (1996) In vivo effect of platelet factor 4 (PF4) and tetrapeptide AcSDKP on haemopoiesis of mice treated with 5-fluorouracil. Br J Haemotol 94: 443–448.
Aviles, A., Alatriste, S., Talavera, A., Delgado, S. & Rosas, A. (1995) Alternating combination chemotherapy and interferon improves survival in poor prognosis multiple myeloma. Clin Oncol R Coll Radiol 7: 97–101.
Calenda, V., Sebahoun, G. & Chermann, J. C. 1992a) Modulation of normal human erythropoietic progenitor cells in long-term liquid cultures after HIV-1 infection. AIDS Res Hum Retroviruses 8: 61–67.
Calenda, V., Tamalet, C. & Chermann, J. C. (1992b) Transient stimulation of granulopoiesis and drastic inhibition of erythropoiesis in HIV-2-infected long-term liquid bone marrow cultures. J Acquired Immune Def Syndr 5: 1148–1157.
Calenda, V., Silvy, F. & Chermann, J. C. (1993) Effects of thymus humoral factor gamma-2 on lymphohaematopoietic progenitor cells: an in vitro study. Res Immunol 144: 395–406.
Cronkite, E. P. & Bullis, J. (1990) In vivo toxicity of 3′-azido-3′-deoxythymidine (AZT) on CBA/Ca mice. Int J Cell Cloning 8: 332–345.
Davey, R. T., Davey, V. J., Metcalf, J. A., Zurlo, J. J., Kovacs, J. A., Falloon, J., Polis, M. A., Zunich, K. M., Masur, H. & Lane, H. C. (1991) A phase I/II trial of zidovudine, interferon-α, and granulocyte–macrophage colony-stimulating factor in the treatment of human immunodeficiency virus type 1 infection. J Infect Dis 164: 43–52.
Donadieu, J., Boutard, P., Bernatowska, E., Tchernia, G., Couillaud, G., Philippe, N. & Le Gall, E. (1997) A European phase II study of recombinant human granulocyte colony-stimulated factor (lenograstim) in the treatment of severe chronic neutropenia in children. Eur J Ped 156: 693–700.
Dorr, R. T. & Fritz, W. L. (1980). Cancer Chemotherapy Handbook. Elsevier North Holland, Inc: New York
Elbein, A. D., Solf, R., Dorling, P. & Vosbeck, K. (1981) Swainsonine: an inhibitor of glycoprotein processing. Proc Natl Acad Sci USA 78: 285–295.
Elion, G. B., Singer, S. & Hitchings, G. H. (1954) Antagonists of nucleic acid derivatives. VIII. Synergism in combinations of biochemically related antimetabolities. J Biol Chem 208: 477–488.
Fischl, M., Galpin, J. E., Levine, J. D., Groopman, J. E., Henry, D. H., Kennedy, P., Miles, S., Robbins, W., Starrett, B., Zalusky, R., Abels, R., Tsai, H. C. & Rudnick, S. A. (1990) Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med 322: 1488–1493.
Gisselbrecht, C., Haioun, C., Lepage, E., Bastion, Y., Tilly, H., Bosly, A., Dupriez, B., Marit, G., Herbrecht, R., Deconinck, E., Marolleau, J-P, Yver, A., Dabouz-Harrouche, F., Coiffier, B. & Reyes, F. (1997) Placebo-controlled phase III study of lenograstim (glycosylated recombinant human granulocyte colony-stimulating factor) in aggressive non-Hodgkin’s lymphoma: Factors influencing chemotherapy administration. Leuk Lymph 25: 289–300.
Goss, P. E., Baptiste, J., Fernandes, B., Baker, M. & Dennis, J. W. (1994) A study of swainsonine in patients with advanced malignancies. Cancer Res 54: 1450–1457.
Hoagland, C. H. (1992). Hematologic complications of cancer chemotherapy. In The Chemotherapy Source Book, Perry MC (ed), pp. 498–507. Williams & Wilkins: Baltimore
Humphries, M. J., Matsumoto, K., White, S. L. & Olden, K. (1986) Oligosaccharide modification by swainsonine treatment inhibits pulmonary colonization of B16-F10 murine melanoma cells. Proc Natl Acad Sci USA 83: 1752–1756.
Hunter, M. G., Bawden, L., Brotherton, D., Graig, S., Cribbes, S., Czaplewski, L. G., Dexter, T. M., Drummond, A. H., Gearing, A. H., Heyworth, C. M., Lord, B. I., McCourt, M., Varley, P. G., Wood, L. M., Edwards, R. M. & Lewis, P. J. (1995) BB-10010: an active variant of human macrophage inflammatory protein-1α with improved pharmaceutical properties. Blood 86: 4400–4408.
Laporte, J. P., Fouillard, L. & Dovay, L. (1991) GM-CSF instead of autologous bone marrow transplantation after BEAM regimen. Lancet 338: 601–602.
Lord, B. I., Dexter, T. M., Clements, J. M., Humter, M. A. & Gearing, A. J. H. (1992) Macrophage-inflammatory protein protects multipotent hematopoietic cells from the cytotoxic effects of hydroxyurea in vivo. Blood 79: 2605–2609.
McLeod, G. X. & Hammer, S. M. (1992) Zidovudine: five years later. Ann Int Med 117: 487–501.
Miles, S. A. (1992) Hematopoietic growth factors as adjuncts to antiretroviral therapy. AIDS Res Hum Retroviruses 8: 1073–1080.
Olden, K., Breton, P., Grzegorzewski, K., Yasuda, Y., Gause, B. L., Oredipe, O. A., Newton, S. A. & White, S. L. (1991) The potential importance of swainsonine in therapy for cancers and immunology. Pharmacol Ther 50: 285–290.
Oredipe, O. A., White, S. L., Grzegorzewski, K., Gause, B. L., Cha, J. K., Miles, V. A. & Olden, K. (1991) Protective effects of swainsonine on murine survival and bone marrow proliferation during cytotoxic chemotherapy. J Natl Cancer Inst 83: 1149–1156.
Perry, M. C. (1992). The Chemotherapy Source Book. Williams & Wilkins: Baltimore
Pratt, W. B., Ruddon, R. W., Ensminger, W. D. & Maybaum, J. (1994). The Anticancer Drugs. Oxford University Press: New York
Richman, D. D., Fischl, M. A., Grieco, M. H., Gottlieb, M. S., Volberding, P. A., Laskin, O. L., Leedom, J. M., Groopman, J. E., Mildvan, D., Hirsch, M. S., Jackson, G. G., Durack, D. T., Phil, D. & Nusinoff-Lehrman, S. (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS-related complex. N Engl J Med 317: 192–197.
Shaunak, S. & Bartlett, J. A. (1989) Zidovudine-induced neutropenia: are we too cautious?. Lancet I: 91–92.
Thompson, M. B., Dunnick, J. K., Sutphin, M. E., Giles, H. D., Irwin, R. D. & Prejean, J. D. (1991) Hematologic toxicity of AZT and ddC administered as single agents and in combination to rats and mice. Fund App Toxicol 17: 159–176.
Tulsiani, D. R. P., Harris, T. & Touster, O. (1982) Swainsonine inhibits the biosynthesis of complex glycoproteins by inhibition of golgi mannosidase II. J Biol Chem 257: 7936–7939.
Tulsiani, D. R. P. & Touster, O. (1983) Swainsonine causes the production of hybrid glycoproteins by human skin fibroblasts and rat liver Golgi preparations. J Biol Chem 258: 7578–7585.
Vose, J. M. & Armitage, J. O. (1992). Bone marrow transplantation. In The Chemotherapy Source Book, Perry MC (ed), pp. 498–507. Williams & Wilkins: Baltimore
Walker, R., Parker, R., Kovacs, J. A., Masur, H., Gralnick, H., Lane, H. C. & Fauci, A. S. (1987) 3′-Azido-3′-deoxythymidine causes red cell aplasia and hypoplasia in AIDS patients with Kaposi’s sarcoma. Clin Res 35: 435A
Watanabe, T., Kelsey, L. S., Yan, Y., Brown, G. S., Jackson, J. D., Ewel, C. & Talmadge, J. E. (1996) In vivo haemoprotective activity of tetrapeptide AcSDKP combined with granulocyte-colony stimulating factor following sublethal irradiation. Br J Haematol 94: 619–627.
Yarchoan, R., Mitsuya, H., Myers, C. E. & Broder, S. (1989) Clinical pharmacology of 3′-azido-2′,3′-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med 321: 726–773.
Zaretsky, M. D. (1995) AZT toxicity and AIDS prophylaxis: Is AZT beneficial for HIV+ asymptomatic persons with 500 or more T4 cells per cubic millimeter?. Genetica 95: 91–101.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Klein, JL., Roberts, J., George, M. et al. Swainsonine protects both murine and human haematopoietic systems from chemotherapeutic toxicity. Br J Cancer 80, 87–95 (1999). https://doi.org/10.1038/sj.bjc.6690326
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690326
Keywords
This article is cited by
-
The study of metabolites from fermentation culture of Alternaria oxytropis
BMC Microbiology (2019)
-
Swainsonine reduces 5-fluorouracil tolerance in the multistage resistance of colorectal cancer cell lines
Molecular Cancer (2007)