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. 1999 Apr;80(1-2):87–95. doi: 10.1038/sj.bjc.6690326

Swainsonine protects both murine and human haematopoietic systems from chemotherapeutic toxicity

J-L D Klein 1,1, J D Roberts 1, M D George 1, J Kurtzberg 2, P Breton 3, J-C Chermann 4, K Olden 1
PMCID: PMC2363022  PMID: 10389983

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 3́-azido-3́-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. © 1999 Cancer Research Campaign

Keywords: swainsonine, cancer, bone marrow, cyclophosphamide, AZT

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Selected References

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  1. Abraham N. G., Chertkov J. L., Staudinger R., Jiang S., Lutton J. D., Argani I., Levere R. D., Kappas A. Long-term bone marrow stromal and hemopoietic toxicity to AZT: protective role of heme and IL-1. Exp Hematol. 1993 Feb;21(2):263–268. [PubMed] [Google Scholar]
  2. Aidoudi S., Guigon M., Lebeurier I., Caen J. P., Han Z. C. In vivo effect of platelet factor 4 (PF4) and tetrapeptide AcSDKP on haemopoiesis of mice treated with 5-fluorouracil. Br J Haematol. 1996 Sep;94(3):443–448. doi: 10.1046/j.1365-2141.1996.d01-1821.x. [DOI] [PubMed] [Google Scholar]
  3. Avilés A., Alatriste S., Talavera A., Delgado S., Rosas A. Alternating combination chemotherapy and interferon improves survival in poor prognosis multiple myeloma. Clin Oncol (R Coll Radiol) 1995;7(2):97–101. doi: 10.1016/s0936-6555(05)80809-x. [DOI] [PubMed] [Google Scholar]
  4. Calenda V., Sebahoun G., Chermann J. C. Modulation of normal human erythropoietic progenitor cells in long-term liquid cultures after HIV-1 infection. AIDS Res Hum Retroviruses. 1992 Jan;8(1):61–67. doi: 10.1089/aid.1992.8.61. [DOI] [PubMed] [Google Scholar]
  5. Calenda V., Silvy F., Chermann J. C. Effects of thymus humoral factor gamma-2 (THF gamma 2) on lymphohaematopoietic progenitor cells: an in vitro study. Res Immunol. 1993 Jul-Sep;144(6-7):395–406. doi: 10.1016/0923-2494(93)80123-g. [DOI] [PubMed] [Google Scholar]
  6. Calenda V., Tamalet C., Chermann J. C. Transient stimulation of granulopoiesis and drastic inhibition of erythropoiesis in HIV-2-infected long-term liquid bone marrow cultures. J Acquir Immune Defic Syndr. 1992;5(11):1148–1157. [PubMed] [Google Scholar]
  7. Cronkite E. P., Bullis J. In vivo toxicity of 3'-azido-3'-deoxythymidine (AZT) on CBA/Ca mice. Int J Cell Cloning. 1990 Sep;8(5):332–345. doi: 10.1002/stem.5530080502. [DOI] [PubMed] [Google Scholar]
  8. Davey R. T., Jr, 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. A phase I/II trial of zidovudine, interferon-alpha, and granulocyte-macrophage colony-stimulating factor in the treatment of human immunodeficiency virus type 1 infection. J Infect Dis. 1991 Jul;164(1):43–52. doi: 10.1093/infdis/164.1.43. [DOI] [PubMed] [Google Scholar]
  9. Donadieu J., Boutard P., Bernatowska E., Tchernia G., Couillaud G., Philippe N., Le Gall E. A European phase II study of recombinant human granulocyte colony-stimulating factor (lenograstim) in the treatment of severe chronic neutropenia in children. Lenograstim Study Group. Eur J Pediatr. 1997 Sep;156(9):693–700. doi: 10.1007/s004310050692. [DOI] [PubMed] [Google Scholar]
  10. ELION G. B., SINGER S., HITCHINGS G. H. Antagonists of nucleic acid derivatives. VIII. Synergism in combinations of biochemically related antimetabolites. J Biol Chem. 1954 Jun;208(2):477–488. [PubMed] [Google Scholar]
  11. Fischl M., Galpin J. E., Levine J. D., Groopman J. E., Henry D. H., Kennedy P., Miles S., Robbins W., Starrett B., Zalusky R. Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med. 1990 May 24;322(21):1488–1493. doi: 10.1056/NEJM199005243222103. [DOI] [PubMed] [Google Scholar]
  12. Gisselbrecht C., Haioun C., Lepage E., Bastion Y., Tilly H., Bosly A., Dupriez B., Marit G., Herbrecht R., Deconinck E. Placebo-controlled phase III study of lenograstim (glycosylated recombinant human granulocyte colony-stimulating factor) in aggressive non-Hodgkin's lymphoma: factors influencing chemotherapy administration. Groupe d'Etude des Lymphomes de l'Adulte. Leuk Lymphoma. 1997 Apr;25(3-4):289–300. doi: 10.3109/10428199709114168. [DOI] [PubMed] [Google Scholar]
  13. Goss P. E., Baptiste J., Fernandes B., Baker M., Dennis J. W. A phase I study of swainsonine in patients with advanced malignancies. Cancer Res. 1994 Mar 15;54(6):1450–1457. [PubMed] [Google Scholar]
  14. Humphries M. J., Matsumoto K., White S. L., Olden K. Oligosaccharide modification by swainsonine treatment inhibits pulmonary colonization by B16-F10 murine melanoma cells. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1752–1756. doi: 10.1073/pnas.83.6.1752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hunter M. G., Bawden L., Brotherton D., Craig S., Cribbes S., Czaplewski L. G., Dexter T. M., Drummond A. H., Gearing A. H., Heyworth C. M. BB-10010: an active variant of human macrophage inflammatory protein-1 alpha with improved pharmaceutical properties. Blood. 1995 Dec 15;86(12):4400–4408. [PubMed] [Google Scholar]
  16. Laporte J. P., Fouillard L., Douay L., Eugene-Jolchine I., Isnard F., Stachowiak J., Najman A., Gorin N. C. GM-CSF instead of autologous bone-marrow transplantation after the BEAM regimen. Lancet. 1991 Sep 7;338(8767):601–602. doi: 10.1016/0140-6736(91)90609-s. [DOI] [PubMed] [Google Scholar]
  17. Lord B. I., Dexter T. M., Clements J. M., Hunter M. A., Gearing A. J. Macrophage-inflammatory protein protects multipotent hematopoietic cells from the cytotoxic effects of hydroxyurea in vivo. Blood. 1992 May 15;79(10):2605–2609. [PubMed] [Google Scholar]
  18. McLeod G. X., Hammer S. M. Zidovudine: five years later. Ann Intern Med. 1992 Sep 15;117(6):487–501. doi: 10.7326/0003-4819-117-6-487. [DOI] [PubMed] [Google Scholar]
  19. Miles S. A. Hematopoietic growth factors as adjuncts to antiretroviral therapy. AIDS Res Hum Retroviruses. 1992 Jun;8(6):1073–1080. doi: 10.1089/aid.1992.8.1073. [DOI] [PubMed] [Google Scholar]
  20. Olden K., Breton P., Grzegorzewski K., Yasuda Y., Gause B. L., Oredipe O. A., Newton S. A., White S. L. The potential importance of swainsonine in therapy for cancers and immunology. Pharmacol Ther. 1991;50(3):285–290. doi: 10.1016/0163-7258(91)90046-o. [DOI] [PubMed] [Google Scholar]
  21. Oredipe O. A., White S. L., Grzegorzewski K., Gause B. L., Cha J. K., Miles V. A., Olden K. Protective effects of swainsonine on murine survival and bone marrow proliferation during cytotoxic chemotherapy. J Natl Cancer Inst. 1991 Aug 21;83(16):1149–1156. doi: 10.1093/jnci/83.16.1149. [DOI] [PubMed] [Google Scholar]
  22. 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. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):192–197. doi: 10.1056/NEJM198707233170402. [DOI] [PubMed] [Google Scholar]
  23. Shaunak S., Bartlett J. A. Zidovudine-induced neutropenia: are we too cautious? Lancet. 1989 Jul 8;2(8654):91–92. doi: 10.1016/s0140-6736(89)90325-5. [DOI] [PubMed] [Google Scholar]
  24. Thompson M. B., Dunnick J. K., Sutphin M. E., Giles H. D., Irwin R. D., Prejean J. D. Hematologic toxicity of AZT and ddC administered as single agents and in combination to rats and mice. Fundam Appl Toxicol. 1991 Jul;17(1):159–176. doi: 10.1016/0272-0590(91)90248-3. [DOI] [PubMed] [Google Scholar]
  25. Tulsiani D. R., Harris T. M., Touster O. Swainsonine inhibits the biosynthesis of complex glycoproteins by inhibition of Golgi mannosidase II. J Biol Chem. 1982 Jul 25;257(14):7936–7939. [PubMed] [Google Scholar]
  26. Tulsiani D. R., Touster O. Swainsonine causes the production of hybrid glycoproteins by human skin fibroblasts and rat liver Golgi preparations. J Biol Chem. 1983 Jun 25;258(12):7578–7585. [PubMed] [Google Scholar]
  27. Watanabe T., Kelsey L. S., Yan Y., Brown G. S., Jackson J. D., Ewel C., Talmadge J. E. In vivo haemoprotective activity of tetrapeptide AcSDKP combined with granulocyte-colony stimulating factor following sublethal irradiation. Br J Haematol. 1996 Sep;94(4):619–627. doi: 10.1046/j.1365-2141.1996.d01-1853.x. [DOI] [PubMed] [Google Scholar]
  28. Yarchoan R., Mitsuya H., Myers C. E., Broder S. Clinical pharmacology of 3'-azido-2',3'-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med. 1989 Sep 14;321(11):726–738. doi: 10.1056/NEJM198909143211106. [DOI] [PubMed] [Google Scholar]
  29. Zaretsky M. D. AZT toxicity and AIDS prophylaxis: is AZT beneficial for HIV+ asymptomatic persons with 500 or more T4 cells per cubic millimeter? Genetica. 1995;95(1-3):91–101. doi: 10.1007/BF01435003. [DOI] [PubMed] [Google Scholar]

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