HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Veiby, O.P. Articles by Olsen, W.M. Search for Related Content PubMed PubMed Citation Articles by Veiby, O.P. Articles by Olsen, W.M.

Inhibition of Enriched Stem Cells in Vivo and in Vitro by the Hemoregulatory Peptide SK&F108636

^a Nycomed Pharma AS, Diagnostica and Exploratory Therapy R&D, Oslo, Norway;
^b SmithKline Beecham Pharmaceuticals, Medicinal Chemistry Dept., King of Prussia, Pennsylvania, USA

Key Words. Stem cells • Hematopoiesis • Hemoregulatory peptide • SK&F108636 • Inhibition

Dr. W.M. Olsen, Nycomed Pharma, Gaustadalléen 21, N-0371 Oslo, Norway.

Replacement of the labile sulfhydryl group (-SH) of the hemoregulatory peptide monomer pyroGluGluAspCysLys (HP5b) with an isosteric methylene group yields a chemically stable compound, SK&F108636. In this study, we describe the effects of SK&F108636 on highly enriched Lin^–Sca1⁺ hematopoietic stem cells. SK&F108636 significantly reduced the fraction of cycling progenitor cells, granulocyte macrophage colony-forming cells (GM-CFC), in vitro and in vivo. There was no effect on GM-CFC or Mix-CFC colony formation. SK&F108636 significantly inhibited proliferation of high proliferative potential (HPP)-CFC in semisolid agar cultures stimulated by stem cell factor + interleukin 3 (IL-3) + IL-1, but had no effect in cultures stimulated with M-CSF + IL-3 + IL-1. SK&F108636 was shown to act directly on the stem cells since SK&F108636 inhibited proliferation of Lin^–Sca1⁺ cells in single cell assays. Administration of SK&F108636 to lethally irradiated mice transplanted with 2000 Lin^–Sca1⁺ cells significantly inhibited proliferation/differentiation of cells developing into colony forming units-spleen (CFU-S) (preCFU-S) and the reconstitution of HPP-CFC and GM-CFC. There was no effect of SK&F108636 on CFU-S colony formation or mature cell regeneration in bone marrow, spleen and blood. Hence, the hemoregulatory peptide monomer SK&F108636 is a potent primitive stem cell inhibitor in vivo and in vitro. Inhibition of stem cell proliferation by small specific inhibitors may protect hematopoiesis from myelotoxic side effects during chemotherapy treatment.