Elevated alpha1-acid glycoprotein in gastric cancer patients inhibits the anticancer effects of paclitaxel, effects restored by co-administration of erythromycin.

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.

Protein-bound polysaccharide K suppresses tumor fibrosis in gastric cancer by inhibiting the TGF-ß signaling pathway.

Peritoneal carcinomatosis (PC) is the most frequent metastatic pattern of gastric cancer and its prognosis is extremely poor. PC is characterized by rich fibrosis and the development of obstructive disorders such as ileus, jaundice and hydronephrosis. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor ß (TGF-ß) has a pivotal function in the progression of EMT. Protein-bound polysaccharide K (PSK) is a biological response modifier that can modulate the TGF-ß/Smad signaling pathway in vitro. In the present study, we established a fibrotic tumor model using human peritoneal mesothelial cells (HPMCs) and a human gastric cancer cell line to evaluate whether PSK attenuates tumor fibrosis. HPMCs exposed to PSK did not undergo the morphological change from a cobblestone-like pattern to a spindle-shape pattern normally induced by treatment with TGF-ß. Immunofluorescence further demonstrated that PSK suppressed TGF-ß-induced overexpression of α-SMA in the HPMCs. We further showed that HPMCs contributed to the proliferation of tumor fibrosis by using a mouse xenograft model. Additionally, PSK treatment of these mice significantly reduced the area of observable tumor fibrosis. These results suggest that seeded cancer cells transformed HPMCs into myofibroblast-like cells through their release of TGF-ß in the microenvironment, facilitating the development of fibrous tumors in organs covered with HPMCs. Therefore, our study indicates that PSK has potential utility as an anti-fibrotic agent in the treatment of gastric cancer patients with PC.

Biodistribution of humanized anti-VEGF monoclonal antibody/bevacizumab on peritoneal metastatic models with subcutaneous xenograft of gastric cancer in mice.

PURPOSE: Vascular endothelial growth factor (VEGF) is correlated with peritoneal metastasis of gastric cancer, increasing vascular permeability accompanied by accumulation of ascites. The aim of the current study is to investigate the biodistribution of bevacizumab in a peritoneal metastatic model of gastric cancer and to clarify which is more suited to treatment of peritoneal metastasis, systemic or regional therapy. METHODS: A highly peritoneal-seeding cell line of gastric cancer, OCUM-2MD3, which exhibited high production and release of VEGF was used in this study. The biodistribution of bevacizumab was investigated using peritoneal metastatic models together with subcutaneous xenografts, and (125)I-radiolabelled bevacizumab was administrated to these models subcutaneously (s.c.) or intraperitoneally (i.p.), respectively. In addition, the anti-tumor response of bevacizumab and paclitaxel was assessed as single agents or in combination using peritoneal metastatic models. RESULTS: In the analysis of biodistribution, (125)I-bevacizumab administrated i.p. indicated low peritoneal clearance. On the other hand, s.c. administration of (125)I-bevacizumab showed preferential accumulation in subcutaneous tumors and peritoneal nodules, with a high blood concentration. In peritoneal metastatic models, the effects of bevacizumab were found for both the growth inhibition of peritoneal nodules (P < 0.01) and the reduction of ascites (P < 0.05). These effects were more prominent by s.c. administration compared with i.p. administration and were increased in combination with i.p. paclitaxel. CONCLUSION: Bevacizumab should be administrated systemically compared to regionally, and the combination with i.p. paclitaxel has a potential to be useful for patients with peritoneal metastasis of gastric cancer.

[A case of stage IV advanced esophageal cancer with a long term survival by radiation therapy combined with nedaplatin and 5-FU chemotherapy].

The patient was a 73-year-old man who complained of dysphagea. Various examinations revealed an esophageal cancer with direct invasion to the left main bronchus (cT4, N2 (104R, 106recR), M0, Stage IVa) and gastric cancer (cT2, N0, M0, Stage IB). The patient was given preoperative chemoradiotherapy (40 Gy/20 fr with CDGP 10 mg/body day 1-5, 8- 12, 15-19 and 5-FU 250 mg/body day 1-5, 8-12, 15-19). After the chemoradiotherapy, we estimated that the esophageal cancer was down stage (cT4-->T3), and that a curative operation was possible. Therefore, subtotal esophagectomy and partial gastrectomy were performed without a complication. Pathological therapeutic evaluation of the esophageal cancer was complete response (CR) and the gastric cancer was T2, N0. Adjuvant chemotherapy was undergone with S-1. However, two years after the first operation, we found a recurrence of gastric duct. Therefore a surgical resection for recurrence of gastric duct was performed. The patient is still alive without recurrence 5 years and 2 months after the first treatment. Radiation therapy combined with nedaplatin and 5-FU is a safe and effective method for treating cT4 advanced esophageal cancer.

[Anti-VEGF therapy for peritoneal dissemination model of gastric cancer considering of pharmacokinetics].

Vascular Endothelial Growth Factor (VEGF) plays an important role in proliferation of cancer cells, angiogenesis and vascular permeability in peritoneal dissemination. Now we investigated the efficacy of anti-VEGF therapy in peritoneal dissemination of gastric cancer considering of pharmacokinetics. We investigated pharmacokinetics of bevacizumab, humanized anti-VEGF monoclonal antibody in subcutaneous xenograft and peritoneal dissemination model of OCUM-2MD3, highly peritoneal-seeding cell line of human scirrhous gastric carcinoma. In the group of intraperitoneal administration, bevacizumab remains in the intraperitoneal cavity and transits slowly to blood pool. On the other hand, in the group of subcutaneous administration, bevacizumab transits faster to blood pool and is accumulated in subcutaneous tumors and peritoneal nodules. Bevacizumab administered intraperitoneally seemed to neutralize intraperitoneal VEGF. Bevacizumab administered in subcutaneous seemed to act on peritoneal wall and control vascular permeability. Systemic administration of anti-VEGF agent will be a potential therapy in peritoneal dissemination of gastric cancer.