Variable effects of tamoxifen on human hematopoietic progenitor cell growth and sensitivity to doxorubicin.
To determine the influence of tamoxifen on the drug sensitivity of normal human hematopoietic progenitor cells, T-cell- and adherent-cell depleted human bone marrow mononuclear cells (T-, Ad-) were exposed in vitro to 5 microM tamoxifen for 24 h. The effects of tamoxifen were highly variable, as exposure to tamoxifen produced an increase (97% +/- 12.3%) in the growth of day-12 committed myeloid progenitors (CFU-GM) in only four of ten experiments utilizing bone marrow from different donors. When T-, Ad- myeloid progenitor cells treated with tamoxifen were subsequently exposed to doxorubicin, 7 of 14 experimental samples studied demonstrated a net increase in the number of surviving clonogenic cells as compared with cells exposed to doxorubicin alone. Tamoxifen also stimulated the growth of a more purified (CD34(+)-selected) progenitor cell population in four of four experiments (by 62.5% +/- 4.9%) but did not increase the survival of these cells upon exposure to doxorubicin; in fact, in five of ten experimental samples, tamoxifen enhanced cell sensitivity to doxorubicin. Taken together, these observations indicate that tamoxifen produces variable stimulation of committed myeloid progenitor cell growth in vitro. Furthermore, while under some circumstances, tamoxifen appears to have the capacity to enhance CFU-GM survival in the presence of doxorubicin, this drug combination may also result in enhanced toxicity to normal bone marrow progenitors.
Woods
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KE
Department of Pharmacology/Toxicology, Medical College of Virginia, Richmond 23298.
Grant
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Yanovich
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Gewirtz
D A
DA
D015703:Antigens, CD / Q000032:analysis / Q000187:drug effects*; D018952:Antigens, CD34; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D013629:Tamoxifen / Q000494:pharmacology*
D015703:Antigens, CD; D018952:Antigens, CD34; D013629:Tamoxifen; D004317:Doxorubicin