A Potential Synergistic Anticancer Effect of Paclitaxel and Amifostine on Endometrial Cancer

Abstract

Although paclitaxel is one of the most effective chemotherapeutic agents, its usefulness is still limited in advanced and recurrent endometrial cancer. Amifostine protection of normal tissues against the side effects of chemotherapeutic agents has been clinically proven in cancer patients; however, its application in endometrial cancer has not been fully evaluated. We have investigated the use of paclitaxel and amifostine in controlling the growth of poorly differentiated endometrial cancer cells, Hec50co, in vitro and in vivo. Our studies show that amifostine had direct anticancer effects on endometrial cancer cells in vitro by arresting the cell cycle at the G 1 phase and inducing apoptosis. Amifostine also inhibited s.c. tumor growth in athymic mice. Paclitaxel IC 50 value was reduced from 14 to 2 nmol/L with pretreatment of a single dose of 178 Mmol/L of amifostine for 72 hours. Amifostine also synergized with paclitaxel in the arrest of the cell cycle at the G 2 -M phase and in the induction of apoptosis. This two-drug regimen inhibited s.c. tumor growth as well as improved mouse survival significantly more than paclitaxel alone. Amifostine also significantly improved paclitaxel-induced cytotoxic effects on peripheral blood profiles. Our studies show that amifostine has direct anticancer effects on endometrial cancer. Our data have also shown a potential anticancer synergy between amifostine and paclitaxel in vitro and in vivo, whereas amifostine maintained a protective role in peripheral blood profiles. The dual specificity of amifostine action should be further investigated. (Cancer Res 2005; 65(20): 9517-24)

Rational combinations of siRNAs targeting Plk1 with breast cancer drugs

“…Antagonism is indicated when c.i.>1, c.i. ¼ 1 indicates an additive effect and a c.i.o1 indicates synergy (Chou and Talalay, 1984;Dai et al, 2005).…”

Amifostine enhancement of the anti-cancer effects of paclitaxel in endometrial cancer is TP53-dependent

“…Cells were exposed to varying concentrations of paclitaxel (2-1,000 nmol/l), amifostine (28 μmol/l-3 mmol/l) for different time periods and the IC 50 values were calculated according to methods previously reported (12). Means and SEs were calculated from at least three experiments.…”

“…Apoptosis study. Apoptotic cells were identified by their fragmented nuclear morphology according to the method previous reported (12). The ratio was obtained as a percentage of apoptotic cells over total cell number in one high magnification field.…”

“…Primary antibodies for p53, p21, Cdk1, Cdk1-T15, and ß-actin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Extracts containing 100 μg of protein/lane were resolved on 12.5% SDS-PAGE gels, transferred to nitrocellulose membranes, probed with primary antibodies, and visualized using enhanced chemiluminescence as described previously (12).…”

“…It was believed that UPSC is a TP53 mutation-driven neoplasm and this group of tumors bypasses the slow hormone-dependent pathway of tumorigenesis but instead undergoes early TP53 alterations that lead to rapid tumor development (10,11). We reported previously that amifostine enhances paclitaxel's therapeutic effect in endometrial cancer in addition to its protective effect in peripheral blood cells (12). In this study, we investigated the p53-dependent mechanism of synergistic effects between amifostine and paclitaxel in two cell lines and two patient tumors representative of the two types of endometrial cancer.…”