Abstract C161: Modulation of thymidine phosphorylase (TP) expression in breast cancer cell lines exposed to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839

Abstract Capecitabine is a potent antitumor drug used in the treatment of many types of cancer such as bowel, breast and stomach cancer. It is administered orally and is first metabolized in the liver by carboxylesterase to generate 5′-deoxy-5-flurocytidine ribose (5′-DFCR) that is subsequently converted to 5′-deoxy-5-fluorouridine ribose (5′-DFUR) by cytidine deaminase. While 5′-DFCR can be further converted to 5′-DFUR in tumor or normal tissues, the conversion of 5′-DFUR to the cytotoxic inhibitor of DNA synthesis 5-FU, is catalyzed by thymidine phosphorylase (TP), which is highly expressed in tumors. Factors modulating the TP levels in tumors are not well understood, however, recent reports suggest that drugs such as taxol and epidermal growth factor receptor (EGFR) inhibitors could induce an increase in TP levels in tumor cells. Here, we sought to determine whether inhibition of EGFR could modulate the levels of TP in a panel of six breast cancer cell lines with varied levels of sensitivity to ZD1839, an EGFR tyrosine kinase inhibitor. Three of the cell lines used in the study (SUM 149, BT474, SKBR3) are commonly classified as sensitive to ZD1839 and the others are known to be moderately sensitive or resistant (MDA-MB 468, BT20, BT549). All cell lines were studied according to two different treatment conditions: either they were provided with DMEM medium supplemented with FBS or starved and subsequently stimulated with 8 nM EGF for 1h. Furthermore, we investigated the in vitro growth inhibitory potency of 5′-DFUR (a Capecitabine metabolite) and ZD1839 in the panel of cell lines. The results showed that: (1) following exposure to 10 µM of ZD1839 for 24h, cells pre-incubated with serum-containing medium did not exhibit a significant change in TP levels. (2) in contrast, all cells starved for 24h and subsequently given 10 µM of ZD1839 for 24h showed varied levels of increase in TP (1.2- to 4.7-fold) except SUM149 in which TP levels remained high, before and after EGF stimulation. BT549, the most ZD1839 resistant cell line showed a low TP expression with no increase after treatment. (3) IC50 values were in agreement with the known levels of sensitivity of all the cell lines ZD1839 and TP expression correlated with cell line sensitivity to 5′DFUR but not to ZD1839. The results in toto suggest that basal and stimulated levels of TP vary among breast cancer cell lines and that EGFR inhibition induces an increase in TP expression in the latter cells. TP induction was mostly seen in cells that were starved, treated with ZD1839 and stimulated with EGF. This suggests that starved cells perhaps synchronized in G0–G1 phase, upon EGF-stimulation may have entered S phase, a cell cycle phase where TP expression is known to reach its maximum. Further studies are ongoing to investigate the sensitivity of the cell panel to ZD1839, 5′DFUR and their corresponding combination. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C161.

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