Purging of acute myeloid leukaemia cells from stem cell grafts by hyperthermia: enhancement of the therapeutic index by the tetrapeptide AcSDKP and the alkyl-lysophospholipid ET-18-OCH(3).
Hyperthermia has been shown to be a potential purging modality in autologous stem cell transplantation settings owing to its selective toxicity towards leukaemic cells. We describe two approaches to further increase the therapeutic index of the hyperthermic purging modality by using normal murine bone marrow cells and a murine model for acute myeloid leukaemia. First, the tetrapeptide AcSDKP was used to protect the normal haematopoietic progenitor cells against hyperthermic damage. Pretreatment for 8 h at 37 degrees C with 1 x 10(-9) mol/l AcSDKP resulted in a decrease in hyperthermic sensitivity of only normal haematopoietic progenitor cells. This combined treatment protocol revealed a therapeutic index (ratio of surviving fractions of normal vs. leukaemic cells) of > 500, which was considered to be sufficient for purging. This was confirmed in vivo by the survival of lethally irradiated recipients transplanted with purged simulated remission bone marrow (1 x 10(6) normal bone marrow cells and 5 x 10(4) leukaemic cells). A further increase of the therapeutic index cells was achieved by the alkyl-lysophospholipid ET-18-OCH(3). An incubation for 4 h at 37 degrees C with 25 microg/ml in the presence of 5% fetal calf serum preferentially enhanced the cytotoxic effect towards the leukaemic stem cell. The combination of AcSDKP and ET-18-OCH(3) with hyperthermia resulted in a therapeutic index of > 5000. This enabled a reduction of the hyperthermic treatment and will further minimize the toxicity to normal haematopoietic stem cell subsets, while a therapeutic index far above the required value is achieved. This tripartite purging treatment therefore offers a safe and fast purging protocol for the elimination of residual leukaemic cells in autografts.
Wierenga
P K
PK
Department of Radiation and Stress Cell Biology, University of Groningen, Groningen, The Netherlands. p.k.wierenga@med.rug.nl
Setroikromo
R
R
Vellenga
E
E
Kampinga
H H
HH
D000208:Acute Disease; D000818:Animals; D016465:Bone Marrow Purging / Q000379:methods*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death; D003114:Colony-Forming Units Assay; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality; D006358:Hot Temperature; D007951:Leukemia, Myeloid / Q000401:mortality / Q000601:surgery*; D051379:Mice; D008808:Mice, Inbred CBA; D023421:Models, Animal; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009842:Oligopeptides / Q000627:therapeutic use; D010742:Phospholipid Ethers / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects; D014182:Transplantation, Autologous
D009842:Oligopeptides; D010742:Phospholipid Ethers; C026659:edelfosine; C058504:goralatide