Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by tamoxifen and other triparanol analogues.
The effects of the triparanol analogues chlorotrianisene, clomiphene, tamoxifen, 5-[p-(fluoren-9-ylidenemethyl)phenyl]-2-piperidineethanol (MDL 10393), MDL 8917v, nafoxidine, 2-[p-(6-methoxy-2-phenylinden-3-yl)phenoxy]triethylamine (U-11555A), 2-[p-(3,4-dihydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]triethylamine (U-10520A), and nitromifene, as well as triparanol itself, were studied in the P388 murine leukemia cell line and in a doxorubicin-resistant subline (P388/ADR). At noninhibitory concentrations, all the analogues increased the sensitivity of P388/ADR cells to doxorubicin but did not have such an effect on the doxorubicin-sensitive cells. Diethylstilbestrol, deacetylated cyclofenil (F6060), hexestrol, and 17 beta-estradiol did not have such an activity. The effects of tamoxifen on doxorubicin sensitivity of P388/ADR cells could not be reversed by 17 beta-estradiol. Estrogen receptors could not be demonstrated in either cell line. It is therefore suggested that the reversal of the doxorubicin-acquired resistance by the triparanol analogues is unrelated to their estrogenic or antiestrogenic activities. The possible clinical implications of these findings are discussed.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D004351:Drug Resistance; D004958:Estradiol / Q000378:metabolism; D007941:Leukemia P388 / Q000473:pathology*; D007942:Leukemia, Experimental / Q000473:pathology*; D051379:Mice; D011960:Receptors, Estrogen / Q000032:analysis; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000494:pharmacology*; D014308:Triparanol / Q000031:analogs & derivatives* / Q000494:pharmacology*
D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; D014308:Triparanol; D004317:Doxorubicin