The synthetic tetrapeptide AcSDKP protects cells that reconstitute long-term bone marrow stromal cultures from the effects of mafosfamide (Asta Z 7654).
The tetrapeptide AcSDKP (Seraspenide) has been described as an inhibitor of CFU-S entry into DNA synthesis; as a result, its administration can protect mice against lethal doses of cytosine arabinoside. We have studied the ability of AcSDKP to protect and promote the growth of early CD34+ human bone marrow (BM) stem cells in Dexter long-term cultures following exposure to a toxic concentration of mafosfamide. The protection assay was based on the preincubation of CD34+ BM cells with or without AcSDKP at 10(-10)M or 10(-8)M followed by exposure to a toxic dose of mafosfamide (100 micrograms/mL). The production of granulomonocytic progenitor cells (CFU-GM) was subsequently studied in long-term bone marrow cultures (LTBMC) of the samples exposed to mafosfamide and preincubated or not (control) with AcSDKP. After a lag of 2 to 3 weeks, the number of CFU-GM peaked at the 4th to 5th week in both the supernatant and the adherent layers. A greater production of granulomonocytic progenitor cells was observed in LTBMC from the samples preincubated with AcSDKP compared with control cells. Depending on the BM samples, enhanced production of CFU-GM in the AcSDKP-treated cell cultures was observed at either the 10(-10)M or 10(-8)M concentration. These results suggest that AcSDKP can protect in vitro human long-term culture-initiating cells (LTC-IC) from mafosfamide, resulting in an increased production of CFU-GM from this early stem cell compartment.
Laboratories Ipsen-Biotech, Paris, France.
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MC
Genevay
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C
Mormont
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F
Thomas
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Berthier
D000595:Amino Acid Sequence; D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000633:toxicity; D015672:Erythroid Precursor Cells / Q000166:cytology; D006098:Granulocytes / Q000166:cytology; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D008264:Macrophages / Q000166:cytology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D009842:Oligopeptides; C048341:mafosfamide; D003520:Cyclophosphamide; C058504:goralatide