Swainsonine protects both murine and human haematopoietic systems from chemotherapeutic toxicity.
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.
Klein
J L
JL
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Roberts
J D
JD
George
M D
MD
Kurtzberg
J
J
Breton
P
P
Chermann
J C
JC
Olden
K
K
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001854:Bone Marrow Cells / Q000187:drug effects; D003520:Cyclophosphamide / Q000009:adverse effects*; D004347:Drug Interactions; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D017026:Swainsonine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000009:adverse effects*
D000276:Adjuvants, Immunologic; D000963:Antimetabolites; D000970:Antineoplastic Agents; D015215:Zidovudine; D003520:Cyclophosphamide; D017026:Swainsonine