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Protection from arabinofuranosylcytosine and n-mustard-induced
myelotoxicity using hemoregulatory peptide pGlu-Glu-Asp-Cys-Lys monomer and
dimer
WR Paukovits, MH Moser, KA Binder and JB Paukovits
Department of Growth Regulation, University of Vienna, Austria.
We have previously shown that the synthetic peptide pGlu-Glu-Asp-Cys- Lys
(pEEDCK monomer) inhibits the cytostatic drug-induced proliferation of
hematopoietic stem cells CFU-S. Keeping CFU-S quiescent by pEEDCK treatment
renders them insensitive to cycle-specific cytostatic drugs and leads to
reduced toxicity. Here we show that pEEDCK application during repeated
(twice) administration of clinically relevant (nonlethal)
1-beta-D-arabinofuranosylcytosine (Ara-C) doses reduced the percentage of
CFU-S in S-phase from 60%-70% to 25%-30% and led to a sustained stem cell
number in the bone marrow (BM), whereas unprotected mice had lost about 75%
of their CFU-S population. Owing to its cysteine content, the pEEDCK
monomer is easily oxidized. The resulting dimer (pEEDCK)2 is a potent
stimulator of hematopoiesis. As we show, it can be used for
postchemotherapy acceleration of hematologic recovery, similar to the use
of recombinant hematopoietic growth factors. A single injection of 30
micrograms/kg pEEDCK monomer to mice 2 hours before the second Ara-C
injection retarded onset of neutropenia (by 2 to 3 days) and improved
recovery after depression. The quantitative degree of neutropenia was not
changed. Postchemotherapy (Ara-C administered twice, followed by N-mustard)
infusion of the stimulatory (pEEDCK)2 dimer (1.4 micrograms/kg/d) produced
a 4.6-fold increase of progenitor levels (6.7 CFU-GM/1,000 BM cells v 1.45
CFU-GM/1,000 in normal mice) 2 days after the end of the cytostatic
treatment when CFU- GM were not detectable in unprotected mice. This
increase was followed after several days by strongly elevated granulocyte
counts, which remained high for approximately 1 week. Up to 75% of the
peripheral leukocytes were mature polymorphonuclear leukocytes (PMN) during
this phase. Ara-C (twice) and monomer treatment as above followed by dimer
infusion resulted in the complete protection of hematopoiesis. Mice treated
with the protective pEEDCK monomer plus stimulatory dimer did not develop
the leukocyte depression noted in unprotected animals. The inhibitory
monomer appears to keep the stem cell population numerically and
qualitatively intact, thus providing optimum target cell conditions for the
subsequent stimulator (dimer) treatment. Our results show that the
hemoregulatory peptide monomer and dimer can be used for improving the
hematologic status of mice treated with clinically relevant doses of
cytostatic drugs (antimetabolite and alkylating, alone and in combination).
Combining both peptides can prevent occurrence of neutropenia completely.
Both peptides can be obtained easily by chemical synthesis and are also
active on human cells. They are thus highly promising candidates for
application as multilevel hemoprotectors in cancer chemotherapy.
Volume 77,
Issue 6,
pp. 1313-1319,
03/15/1991
Copyright © 1991 by The American Society of Hematology
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