Enhanced selectivity of hyperthermic purging of human progenitor cells using Goralatide, an inhibitor of cell cycle progression.
Recurrence of leukemia is a major problem after autologous stem cell transplantation. One potential means of reducing this risk is to purge the autologous transplant in vitro by hyperthermia. We have demonstrated that after a hyperthermic treatment of 120 min at 43 degrees C, the leukemic progenitor cells (CFU-AML) are decreased by 5-log but the normal hematopoietic committed progenitor cells (CFU-GM, BFU-E and CFU-E) are reduced by only 1-log. Moreover, the hyperthermic sensitivity coincides with the stem cell hierarchy, ie CFU-GM are less heat sensitive than BFU-E, while CFU-E are the most sensitive. The impact of pretreatment with the tetrapeptide AcSDKP (Goralatide) on the proliferative activity and heat sensitivity of the normal and leukemic progenitor cells was determined. An incubation of 21 h at 37 degrees C with 10(-9) M Goralatide reduces the number of normal hematopoietic progenitor cells in S-phase and concomitantly decreases their hyperthermic sensitivity. This effect implies that the proliferative activity is the major determinant for the detected differences in hyperthermic sensitivity of the subsets in the normal hematopoietic stem cell compartment. In contrast, the cell cycle progression of leukemic progenitor cells is not affected and hence these cells are not protected from hyperthermia-induced cell killing after preincubation with Goralatide. Thus, the treatment with Goralatide increases the therapeutic window of hyperthermia and increases the potential value of this physical purging technique.
Wierenga
P K
PK
Department Radiobiology, University of Groningen, The Netherlands.
Brenner
M K
MK
Konings
A W
AW
D002453:Cell Cycle / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006358:Hot Temperature; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*
D006131:Growth Inhibitors; D009842:Oligopeptides; C058504:goralatide