In vivo modifications of AcSDKP metabolism and haematopoiesis in mice treated with 5-fluorouracil and Goralatide.

Abstract

The tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP), a physiological inhibitor of the proliferation of haematopoietic stem cells, is degraded by the angiotensin-I-converting enzyme (ACE). Whereas synthetic AcSDKP (Goralatide) protects normal mice from the haematological toxicity of chemotherapy, it has a lower beneficial effect in humans. This discrepancy could be dependent on Goralatide administration schedules, as well as on the endogenous concentrations of AcSDKP and ACE, which vary during chemotherapy. We investigated the effect of one myelotoxic dose of 5-fluorouracil (5-FU, 200 mg kg-1) administered without or with Goralatide on blood, bone marrow (BM) and spleen AcSDKP concentrations, ACE activity, nucleated cell counts and survival of the primitive haematopoietic progenitors high proliferative potential colony-forming cells (HPP-CFCs). The 5-FU treatment dramatically decreased the BM concentrations of AcSDKP by 73% and increased the ACE activity in plasma by 50% during the period of active BM regeneration. Repeated injections of Goralatide from 24 h before to 36 h after the i.p. injection of 5-FU spared BM HPP-CFCs. As an injection of 10 mg of Goralatide induced a short peak of plasma AcSDKP without modifying its BM concentrations, we suggest that its protective effect on HPP-CFCs could be mediated by its interference with other plasma molecules targeting to the BM. By improving our knowledge of the biology of AcSDKP in vivo during chemotherapy, our results could help to better define the therapeutic use of Goralatide.