Plasma interacts with mafosfamide toxicity to normal haematopoietic progenitor cells: impact on in vitro marrow purging.
Bone marrow purging with cyclophosphamide derivatives in autologous bone marrow transplantation has demonstrated that the killing of leukemic cells and simultaneous preservation of normal progenitor cells depends on a number of parameters, in particular the haematocrit, nucleated cell concentration and nature of the cells. We have previously described a reliable experimental procedure for in vitro bone marrow treatment, based on individual adjustment of the drug dosage. The present study reveals an inhibitory action of plasma on the toxicity of mafosfamide to normal haematopoietic progenitor cells. In an initial series of 42 successive patients, determination of the CFU-GM lethal dose 95% (CFU-GM LD 95) showed this parameter to be inversely correlated to the nucleated cell concentration (NCC) (p < 0.001). Assuming the plasma content of the buffy coat cells (BC) to be higher in the less rich marrow samples, we then investigated the role of plasma in progenitor cell sensitivity to the drug. Results were as follows: (1) in the presence of 60% autologous or allogeneic plasma, CFU-GM LD 95 was increased by a factor of 2.18 +/- 0.35 or 1.98 +/- 0.23 respectively as compared to controls in a solution of 2% bovine serum albumin (p = 0.014), (2) this observation remained valid whatever the origin of the plasma and (3) the same was true whatever the nature of the cells, derived from normal donors or patients with haematological malignancies. These data suggest that plasma contains an inhibitor(s) of mafosfamide.(ABSTRACT TRUNCATED AT 250 WORDS)
Giarratana
M C
MC
Unité de recherceh sur les greffes de cellules souches hématopoïétiques, CHU Saint-Antoine, Paris, France.
Gorin
N C
NC
Douay
L
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D016465:Bone Marrow Purging; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*
C048341:mafosfamide; D003520:Cyclophosphamide