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The tetrapeptide AcSDKP specifically blocks the cycling of primitive normal
but not leukemic progenitors in long-term culture: evidence for an indirect
mechanism
JD Cashman, AC Eaves and CJ Eaves
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
In the present study, we investigated the ability of the tetrapeptide
NAc-Ser-Asp-Lys-Pro-OH (AcSDKP), a reported inhibitor of primitive
hematopoietic cells, to influence the proliferative behavior of primitive
normal and chronic myeloid leukemia (CML) progenitor cells in the adherent
layer of long-term cultures (LTCs). Addition of > or = 50 ng/mL of
AcSDKP to LTCs of normal cells at the time of the regular weekly
half-medium change selectively and reversibly decreased the proportion of
high proliferative potential erythroid and granulopoietic progenitors in
the adherent layer that were in S-phase without changing their numbers, but
had no effect on either the cycling activity or number of analogous
(neoplastic) cells in the adherent layer of CML LTCs. Specificity of the
effect of AcSDKP on primitive normal progenitors was demonstrated by the
finding that a similar addition of either the control peptide, AcSDKE, or
100 ng/mL of tumor necrosis factor-alpha (TNF-alpha, which contains the
SDKP sequence), or SDKP itself (at 300 ng/mL) did not inhibit the
proliferation of primitive normal progenitors in LTC adherent layers.
Incorporation of > or = 30 ng/mL of AcSDKP (but not the related control
peptide, AcSDKE) directly into methylcellulose cultures of normal marrow
cells resulted in a dose- dependent suppression of colony formation, which
was not seen in similar studies with CML marrow or after removal of
adherent cells from normal marrow. Additional experiments showed that the
inhibitory effect of AcSDKP on primitive normal progenitor cycling in the
LTC system could be overcome by the simultaneous addition of macrophage
inflammatory protein-1 beta (MIP-1 beta); an antagonist of MIP-1 alpha. The
apparent differential effect of AcSDKP on primitive normal and CML
progenitors may thus be a secondary consequence of the differential
responsiveness of these cells to MIP-1 alpha for another molecule
antagonized by MIP-1 beta), whose production or release by adherent marrow
cells is inducible by AcSDKP. Such a mechanism may offer a method for
obtaining localized increases in vivo of cytokines like MIP- 1 alpha,
suggesting novel and perhaps less toxic strategies for protecting primitive
normal progenitors during repeated treatments with cycle-active
chemotherapeutic agents where escalating the dose of drug given would be
desirable.
Volume 84,
Issue 5,
pp. 1534-1542,
09/01/1994
Copyright © 1994 by The American Society of Hematology
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