Reduction of heat‐induced haemotoxicity in a hyperthermic purging protocol of murine acute myeloid leukaemic stem cells by AcSDKP

• Published in: British journal of haematology 1997-12, Vol.99 (3), p.692-698
• Main Authors: Wierenga, Pieter K., Dillingh, Jan H., Konings, Antonius W. T.
• Format: Article
• Language: English
• Subjects: AcSDKP; Acute Disease; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Bone Marrow Purging; bone marrow transplantation; Bone marrow, stem cells transplantation. Graft versus host reaction; Female; Goralatide; Growth Inhibitors - therapeutic use; haemopoiesis; Hematologic and hematopoietic diseases; Hematologic Diseases - pathology; Hematologic Diseases - prevention & control; Hematopoiesis - physiology; hyperthermia; Hyperthermia, Induced; Leukemia, Myeloid - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Oligopeptides - therapeutic use; purging; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumor Cells, Cultured
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.1997.4403251.x

The tetrapeptide AcSDKP (Goralatide) is a cytokine with known inhibitory effects on cell proliferation. Many purging agents used in autologous bone marrow transplantation protocols, including hyperthermia, preferentially kill cycling cells. A pretreatment with Goralatide offers a possibility to reduce the haemotoxicity in many purging settings. The impact of Goralatide on the hyperthermic purging protocol was investigated in normal and myeloid leukaemic (SA8) murine cells. The median survival time after transplantation (i.e. leukaemia incidences) was used as an in vivo parameter to determine the effects on leukaemic cells. The hyperthermic effect on normal and leukaemic cells was also investigated in vitro using the cobblestone area‐forming cell (CAFC) assay. A heat treatment of 90 min at 43°C resulted in a 4‐log depletion of leukaemic stem cells. For normal progenitor cells (CFU‐GM) a 2‐log cell kill was shown. The reduction in proliferative activity of the CFU‐GM after an 8 h incubation with 10−9 m Goralatide resulted in a decrease in the heat sensitivity of the progenitor subset to approximately a 1‐log cell kill. The leukaemic precursor cells seem insensitive to Goralatide inhibition, implicating an increase in the therapeutic window of the hyperthermic purging protocol. Finally, simulated remission bone marrow (5% leukaemic blasts) was incubated with Goralatide followed by a heat treatment of 90 min at 43°C. Lethally irradiated (10 Gy) mice transplanted with heat‐treated remission bone marrow (106 normal bone marrow cells versus 5 × 104 leukaemic cells) died of aplasia while Goralatide‐pretreated remission bone marrow could rescue the irradiated mice without revealing leukaemic engraftment. These findings confirmed the enhanced protection against hyperthermia of the normal haemopoietic subsets by Goralatide and thus increased the success of the hyperthermic purging protocol.