title: Effect of melphalan against self-renewal capacity of leukemic progenitors in acute myeloblastic leukemia.
abstract: This study aimed to evaluate the effect of melphalan on both terminal divisions and self-renewal capacity of acute myeloblastic leukemia (AML) progenitors (colony-forming units, CFU-L) grown in methylcellulose. Terminal divisions and self-renewal were assayed by primary (PE1) and secondary (PE2) colony formation, respectively. Thirteen cases of AML, were tested. Melphalan induced a negative exponential dose-effect on CFU-L survival. Moreover, melphalan was equally effective in inhibiting CFU-L growth in both PE1 and PE2 assays, with D10 values of 1.53 +/- 0.17 micrograms/ml and 1.59 +/- 0.21 micrograms/ml for PE1 and PE2, respectively (p = 0.48). Cytotoxicity of melphalan on CFU-L did not differ significantly from that observed for normal hemopoietic granulocyte-macrophage colony-forming units, erythroid burst-forming units, and granulocyte-erythroid-macrophage-megakaryocyte progenitors. Mafosfamide-lysine, a stable cyclophosphamide congener, strongly inhibited primary colony formation (PE1) with a D10 value of 14.46 +/- 1.76 micrograms/ml, but was much less efficient in the PE2 assay. Our findings suggest that the self-renewal capacity of AML progenitors can be differentially affected by alkylating agents. Moreover, since it is now considered that chemotherapy should be preferentially directed against the self-renewal of leukemic progenitors, melphalan might offer a greater potential than cyclophosphamide or cyclophosphamide derivatives in the therapy of AML.
authors.affiliation: Laboratoire d'Hématologie et de Génétique, Centre Regional de Transfusion Sanguine, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Demur
authors.forename: M
authors.initials: M
authors.lastname: Chiron
authors.forename: S
authors.initials: S
authors.lastname: Saivin
authors.forename: M
authors.initials: M
authors.lastname: Attal
authors.forename: N
authors.initials: N
authors.lastname: Dastugue
authors.forename: C
authors.initials: C
authors.lastname: Bousquet
authors.forename: J L
authors.initials: JL
authors.lastname: Galinier
authors.forename: P
authors.initials: P
authors.lastname: Colombies
authors.forename: G
authors.initials: G
authors.lastname: Laurent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008558:Melphalan / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; C048341:mafosfamide; D003520:Cyclophosphamide; D008558:Melphalan