PMID- 8068944
OWN - NLM
STAT- MEDLINE
DCOM- 19940928
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 84
IP  - 5
DP  - 1994 Sep 1
TI  - The tetrapeptide AcSDKP specifically blocks the cycling of primitive normal but 
      not leukemic progenitors in long-term culture: evidence for an indirect 
      mechanism.
PG  - 1534-42
AB  - 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.
FAU - Cashman, J D
AU  - Cashman JD
AD  - Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
FAU - Eaves, A C
AU  - Eaves AC
FAU - Eaves, C J
AU  - Eaves CJ
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Chemokine CCL4)
RN  - 0 (Cytokines)
RN  - 0 (Macrophage Inflammatory Proteins)
RN  - 0 (Monokines)
RN  - 0 (Oligopeptides)
RN  - 0 (Recombinant Proteins)
RN  - H041538E9P (goralatide)
RN  - VC2W18DGKR (Thymidine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Bone Marrow/pathology
MH  - Bone Marrow Cells
MH  - Cell Adhesion
MH  - Cell Cycle/*drug effects
MH  - Chemokine CCL4
MH  - Colony-Forming Units Assay
MH  - Culture Techniques/methods
MH  - Cytokines/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Hematopoietic Stem Cells/cytology/*drug effects/pathology
MH  - Humans
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*pathology
MH  - Macrophage Inflammatory Proteins
MH  - Molecular Sequence Data
MH  - Monokines/pharmacology
MH  - Oligopeptides/*pharmacology
MH  - Recombinant Proteins/pharmacology
MH  - Reference Values
MH  - S Phase/drug effects
MH  - Thymidine/metabolism
MH  - Time Factors
EDAT- 1994/09/01 00:00
MHDA- 1994/09/01 00:01
CRDT- 1994/09/01 00:00
PHST- 1994/09/01 00:00 [pubmed]
PHST- 1994/09/01 00:01 [medline]
PHST- 1994/09/01 00:00 [entrez]
AID - S0006-4971(20)77623-8 [pii]
PST - ppublish
SO  - Blood. 1994 Sep 1;84(5):1534-42.