Reduced tamoxifen accumulation is not associated with stimulated growth in tamoxifen resistance

Abstract

To study tamoxifen resistance-stimulated growth, 30 female ovariectomized nude mice were implanted with tamoxifen-resistant tumors and treated with 10-1000 micrograms/day of tamoxifen citrate subcutaneously. Tamoxifen stimulated MCF-7 tumor growth in a dose-dependent manner, with tumoral tamoxifen concentrations increasing proportionally to the dose (1-13 nmol/g), as measured by high-performance liquid chromatography (HPLC). Flow-cytometric analysis revealed that tamoxifen-resistant tumors had a different DNA content as compared with wild-type MCF-7 cells. In contrast to earlier results, these data suggest that tamoxifen resistance-stimulated growth is associated with increasing rather than decreasing tumoral tamoxifen concentrations. Furthermore, the observed ploidy changes in the tamoxifen-resistant tumors imply that a genetic basis may exist for the development of tamoxifen resistance.

Biomonitoring of urinary tamoxifen and its metabolites from breast cancer patients using nonaqueous capillary electrophoresis with electrospray mass spectrometry

“…Urine samples were chosen for these preliminary investigations because they could be obtained noninvasively. Although many explanations have been proposed for tamoxifen resistance in patients [13], the mechanisms for clinical resistance to tamoxifen are still not yet fully established [11][12][13][14][15][16][17]53]. Among the leading explanations for acquired tamoxifen resistance is variability in tamoxifen metabolism among patients and within breast tumors.…”

“…However, despite these proven benefits for treated populations, tamoxifen's use is limited by the eventual development of acquired tamoxifen resistance in many patients. Many explanations for this therapeutic failure have been proposed, including interpatient and intratumoral variations in tamoxifen metabolism, but this has not yet been definitively established [11][12][13][14][15][16][17].…”