THE TETRAPEPTIDE ACETYL-N-SER-ASP-LYS-PRO (GORALATIDE) PROTECTS FROM DOXORUBICIN-INDUCED TOXICITY - IMPROVEMENT IN MICE SURVIVAL AND PROTECTION OF BONE-MARROW STEM-CELLS AND PROGENITORS

The tetrapeptide Acetyl-N-Ser-Asp-Lys-Pro (AcSDKP or Goralatide), a ph ysiological regulator of hematopoiesis, inhibits the entry into the S- phase of murine and human hematopoietic stem cells. It has been shown to reduce the damage to specific compartments in the bone marrow resul ting from treatment with chemotherapeutic agents, ionizing radiations, hyperthermy, or phototherapy. The present study was performed to asse ss the therapeutic potential of AcSDKP in vivo in reducing both the to xicity and the hematopoietic damage induced by fractionated administra tion of doxorubicin (DOX), a widely used anticancer drug. Here we show ed that AcSDKP could reduce COX-induced mortality in mice and could pr otect particularly the long-term reconstituting cells (LTRCs) in addit ion to colony forming units-spleen, high proliferative potential colon y-forming cells, and colony-forming units-granulocyte-macrophage (CFU- GM) from DOX toxicity. The protection against COX-induced mortality in mice was improved when AcSDKP was administered for 3 days, at a dose of 2.4 mu g/d, by continuous subcutaneous (SC) infusion or fractionate d SC injections starting 48 hours before DOX treatment. Moreover, the recovery of the CFU-GM population in the AcSDKP-DOX-treated mice was o ptimized by the subsequent administration of granulocyte colony-stimul ating factor (G-CSF). The coadministration of AcSDKP with DOX may impr ove its therapeutic index by reducing both acute hematotoxicity on lat e stem cells and progenitors and long-term toxicity on LTRCs. Optimiza tion of these treatments combined with G-CSF may provide an additional approach to facilitate hematopoietic recovery after cancer chemothera py. (C) 1998 by The American Society of Hematology.