THE TETRAPEPTIDE ACSDKP REDUCES THE SENSITIVITY OF MURINE CFU-MK AND CFU-GM PROGENITORS TO ARACYTINE IN-VITRO AND IN-VIVO

The tetrapeptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP) has been described as an inhibitor of CFU-S entry into DNA synthesis; as a result, its admi nistration can protect mice against lethal doses of cytosine arabinosi de (Ara-C). In the present study, we tested the protective effect of A cSDKP on CFU-MK and CFU-GM progenitor cells in mice treated at lower d oses of Ara-C more relevant to human clinical situations. Firstly, we report for the first time that in vitro pre-incubation of murine BM MN C with AcSDKP at concentrations of 10(-10) and 10(-9) M for 48 h decre ased CFU-MK, in parallel to CFU-GM, progenitor growth. This resulted i n an increase of recovery of these progenitors after exposure to Ara-C . Secondly, we tested the effect of AcSDKP on progenitor cells in vivo in different conditions in Ara-C treated mice. We show that the admin istration of AcSDKP before starting Ara-C treatment resulted in a sign ificant increase in progenitor CFU-GM, CFU-MK and mature MK numbers, 6 and 8 days after the first Ara-C injection. Interestingly, no differe nce was observed whether AcSDKP was started 24 or 48 h before Ara-C. I n a protocol in which AcSDKP was administered for 8 days starting 48 h before Ara-C treatment,the dose did not appear to be critical at leas t within the range tested (4 vs. 40 mu g/injection). In addition, the administration of AcSDKP at 64 mu g/kg per injection for 5 days and st opping it 3 days before the end of Ara-C treatment, i.e. five instead of eight applications, further increased its protective effect. Thus o ur results demonstrate protective effect of AcSDKP for progenitors dur ing a fractionated protocol of Ara-C treatment and indicates an import ance of the dose and the schedule of administration of AcSDKP in desig ning future clinical trials. (C) 1998 Published by Elsevier Science Ir eland Ltd. All rights reserved.