Toxicity of idarubicin and doxorubicin towards normal and leukemic human bone marrow progenitors in relation to their proliferative state.
The effect of growth stimulation on the sensitivity of normal and leukemic human bone marrow progenitors to idarubicin and doxorubicin was studied. Clonogenic assays from colony-forming units of the granulocyte-macrophage lineage (CFU-GM) and leukemic clonogenic cells (CFU-L) were applied using human placenta conditioned medium (HPCM) as source of growth factors. Before seeding cells in clonogenic assay they were exposed to the anthracyclines for 2 h without preincubation, or following a 48 h preincubation period in the presence of HPCM. Drug concentrations used ranged from 0.001-0.1 microgram/ml for idarubicin and from 0.1-1.5 microgram/ml for doxorubicin. In addition, a limited number of bone marrow samples were exposed to the cytostatically active metabolite of idarubicin; idarubicinol (Idol; range 0.001-0.1 microgram/ml). Proliferation of CFU-GM and CFU-L during 48 h was measured by iododeoxyuridine (IdUrd) incorporation. Spontaneous proliferation of CFU-GM increased from 38 to 88% after 48 h stimulation by HPCM. The mean number of proliferating CFU-L increased from 40 to 77% when stimulated with HPCM. Doxorubicin inhibited colony formation of CFU-GM and CFU-L to 50% (IC50CFU-GM, IC50CFU-I) at mean concentrations of 0.355 microgram/ml and 0.103 microgram/ml when applied before preincubation with HPCM, and 0.108 microgram/ml and 0.055 microgram/ml when applied after preincubation. Idarubicin appeared the most potent drug in all experiments regardless of the preincubation procedure or sample origin, with average IC50CFU-GM and IC50CFU-L of 0.008 microgram/ml and 0.006 microgram/ml, respectively, when applied before preincubation with HPCM, and 0.006 microgram/ml and 0.005 microgram/ml when applied after preincubation with HPCM. Idarubicinol showed intermediate potency with average IC50CFU-GM of 0.022 microgram/ml and 0.023 microgram/ml when applied before and after preincubation with HPCM, respectively. In order to assess the effect of growth stimulation on drug sensitivity, samples were evaluated pair-wise (sensitivity of the same sample before vs. after preincubation with HPCM) and were submitted to the Wilcoxon test for matched pairs. Statistically significant enhancement of cytotoxicity was demonstrated for Doxorubicin vs. CFU-GM (p < or = 0.021) and a strong trend versus CFU-L (p = 0.06). The data further demonstrate that proliferation-dependency of doxorubicin toxicity is more pronounced for CFU-GM than for CFU-L. These data also show that idarubicin and idarubicinol toxicity is proliferation-independent. Idarubicin is relatively more potent than doxorubicin in suppressing the growth potential of low or nonproliferating progenitors.(ABSTRACT TRUNCATED AT 400 WORDS)
Minderman
H
H
Department of Internal Medicine, University Hospital Nijmegen, The Netherlands.
Linssen
P
P
van der Lely
N
N
Wessels
J
J
Boezeman
J
J
de Witte
T
T
Haanen
C
C
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004317:Doxorubicin; C054440:idarubicinol; D015255:Idarubicin; D003630:Daunorubicin