M P Liu1, R E Handschumacher. 1. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Abstract
PURPOSE: To correlate changes in uridine transport and colony morphology with differentiation of human breast cancer cells by tamoxifen and related agents. MATERIALS AND METHODS: Cultures of MCF-7 human breast cancer were treated with estradiol or the antiestrogen derivatives tamoxifen, hydroxytamoxifen, and ICI 164, 384. Initial rates of uridine transport and equilibrium concentrations were determined and morphological characteristics of the cultures evaluated. RESULTS: Tamoxifen causes an early induction of a Na+ -dependent transport of uridine characteristic of normal epithelial cells but absent in normal MCF-7 cultures and most human neoplasms examined. The pure antiestrogen ICI 164,384 and the more potent 4-hydroxytamoxifen also induced concentrative uridine transport; estradiol could prevent the expression of this transporter. Associated with induction of transport was a dramatic increase in dome formation in the cultures, a measure of unidirectional inorganic ion transport characteristic of the differentiated state. CONCLUSIONS: The induction of a concentrative transport of uridine is a concomitant of cellular differentiation of breast tumor cells. These findings give added weight to evidence that uridine may play a regulatory role in the transition to the neoplastic state. The absence of the transporter and low intracellular uridine concentrations in the undifferentiated state may relate to 5-FU sensitivity of breast tumors. Induction of the transporter by tamoxifen and the consequent major increase in intracellular concentrations of free uridine suggests a potentially negative effect of tamoxifen on regimens containing 5-FU.
PURPOSE: To correlate changes in uridine transport and colony morphology with differentiation of humanbreast cancer cells by tamoxifen and related agents. MATERIALS AND METHODS: Cultures of MCF-7 humanbreast cancer were treated with estradiol or the antiestrogen derivatives tamoxifen, hydroxytamoxifen, and ICI 164, 384. Initial rates of uridine transport and equilibrium concentrations were determined and morphological characteristics of the cultures evaluated. RESULTS:Tamoxifen causes an early induction of a Na+ -dependent transport of uridine characteristic of normal epithelial cells but absent in normal MCF-7 cultures and most humanneoplasms examined. The pure antiestrogen ICI 164,384 and the more potent 4-hydroxytamoxifen also induced concentrative uridine transport; estradiol could prevent the expression of this transporter. Associated with induction of transport was a dramatic increase in dome formation in the cultures, a measure of unidirectional inorganic ion transport characteristic of the differentiated state. CONCLUSIONS: The induction of a concentrative transport of uridine is a concomitant of cellular differentiation of breast tumor cells. These findings give added weight to evidence that uridine may play a regulatory role in the transition to the neoplastic state. The absence of the transporter and low intracellular uridine concentrations in the undifferentiated state may relate to 5-FU sensitivity of breast tumors. Induction of the transporter by tamoxifen and the consequent major increase in intracellular concentrations of free uridine suggests a potentially negative effect of tamoxifen on regimens containing 5-FU.