Cytotoxicity of chlorambucil and chlorambucil-fatty acid conjugates against human lymphomas and normal human peripheral blood lymphocytes.
The cytotoxic activity of chlorambucil (Chl) and of chlorambucil-fatty acid conjugates of different degree of unsaturation have been assayed in vitro upon two human lymphoma cell lines and comparatively, upon quiescent and mitogen-activated lymphocytes from healthy blood donors. The cell toxicity observed with Chl-arachidonic acid and Chl-docosahexaenoic acid against lymphoma cells was, at any experimental condition used, equal or higher than the individual toxic potential of either chlorambucil or fatty acids. The two conjugates, like chlorambucil alone, were toxic against mitogen-activated lymphocytes. Contrary to chlorambucil, Chl-arachidonic at any concentration tested, lacked of toxicity towards normal non-activated lymphocytes. Chl-oleic acid conjugate was, whatever the cell species tested, much less toxic than Chl alone. In conclusion, the coupling of chlorambucil with polyunsaturated fatty acids increases: (a) the selectivity against neoplastic versus quiescent lymphocytes and (b) the toxicity for B-lymphoma cells. The selective effect of Chl-fatty acid conjugates is discussed in relation with the expression of an AFP/AFP-receptor autocrine system in malignant lymphoblastoid cells and in mitogen-activated lymphocytes.
Anel
A
A
Laboratoires de Chimie des Protéines et de Chemie Organique Biologique, Institut de Recherches Scientifiques sur le Cancer, Villejuif, France.
Halmos
T
T
Torres
J M
JM
Piñeiro
A
A
Antonakis
K
K
Uriel
J
J
D001095:Arachidonic Acids / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004281:Docosahexaenoic Acids / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008223:Lymphoma / Q000188:drug therapy*; D009829:Oleic Acids / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001095:Arachidonic Acids; D009829:Oleic Acids; C065769:chlorambucil-docosahexaenoic acid conjugate; C065768:chlorambucil-oleic acid conjugate; C065767:chlorambucil-arachidonic acid conjugate; D002699:Chlorambucil; D004281:Docosahexaenoic Acids