Abstract
Paclitaxel (PTX) which easily elutes into ascites is widely used to treat gastric cancer patients with peritoneal carcinomatosis (PC), but clinical outcomes are suboptimal. Increased concentrations of α1-acid glycoprotein (AGP), an important drug-binding protein, have been reported in the plasma and ascites of cancer patients. This study sought to clarify whether AGP binds to PTX and alters its anticancer effects. AGP concentrations were measured in the serum and ascites of gastric cancer patients with PC and in the serum of healthy volunteers. The in vitro effects of AGP and AGP plus erythromycin (EM) on PTX were evaluated by MTT assays in the gastric cancer cell lines. We also measured AGP concentrations in the ascites of PC model mice and examined the effects of EM plus PTX on PC. The mean AGP concentrations in the serum and ascites of gastric cancer patients with PC were 1524 and 834 μg/mL, respectively, higher than the mean AGP concentration of 650 μg/mL observed in the sera of healthy volunteers. AGP > 400 μg/mL significantly suppressed the cell growth inhibitory effect of PTX in vitro, but the co-administration of EM restored it. Elevated AGP concentrations were observed in the ascites of PC model mice. Administration of PTX alone did not markedly diminish PC, whereas co-administration of PTX and EM significantly reduced PC (p = 0.011). AGP is an important regulatory factor modulating the anticancer activity of intraperitoneal PTX. The co-administration of PTX and EM may be effective in treating gastric cancer patients with PC.
Highlights
Gastric cancer is one of the most common malignant diseases worldwide [1]
A comparison of serum acid glycoprotein (AGP) concentrations in cancer patients with peritoneal carcinomatosis (PC) and healthy volunteers found that AGP concentrations were about 2.5-fold higher in the formers than in the latters (1524 ± 586 vs. 650 ± 158 lg/mL, p = 0.0049) (Fig. 1)
The mean concentration of AGP was higher in ascites of gastric cancer patients with PC than in the serum of healthy volunteer, this difference was not statistically significant
Summary
Gastric cancer is one of the most common malignant diseases worldwide [1]. mortality rates have declined, advanced gastric cancer remains life-threatening [2]. Intraperitoneal PTX (IP PTX) has been reported successful in several patients [7, 8], prompting the ongoing phase III PHOENIX-GC trial, assessing the effectiveness of IP PTX in gastric cancer patients with PC. It has not been recognized as a standard chemotherapy, and intravenous PTX is a standard now. The randomized phase II JCOG0407 (Japan Clinical Oncology Group) trial was conducted to test the effects of weekly intravenous PTX as second-line treatment in which gastric cancer patients with PC, reported an MST of 7.7 months [9]. Intravenous PTX has not shown satisfactory clinical outcomes in gastric cancer patients with PC
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