Effect of melphalan against self-renewal capacity of leukemic progenitors in acute myeloblastic leukemia

• Published in: Leukemia Vol. 6; no. 3; p. 204
• Main Authors: Demur, C, Chiron, M, Saivin, S, Attal, M, Dastugue, N, Bousquet, C, Galinier, J L, Colombies, P, Laurent, G
• Format: Journal Article
• Language: English
• Published: England 01.03.1992
• Subjects: Antineoplastic Agents - pharmacology; Cell Division - drug effects; Cell Survival - drug effects; Cyclophosphamide - analogs & derivatives; Cyclophosphamide - pharmacology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Humans; Leukemia, Myeloid, Acute - pathology; Melphalan - pharmacology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - pathology; Tumor Stem Cell Assay
• ISSN: 0887-6924

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.