Gemcitabine suppresses malignant ascites of human pancreatic cancer: correlation with VEGF expression in ascites.
It has been reported that vascular endothelial growth factor (VEGF) is a potent angiogenic factor that also has the ability to increase vascular permeability. VEGF plays an important role in the development of malignant ascites in various cancers. Gemcitabine has been prescribed for patients with inoperable human pancreatic ductal carcinoma as a first-line chemotherapy. However, the response rates of patients with malignant ascites who were undergoing systemic chemotherapy were extremely limited. In the present study, we investigated the role of VEGF and the effects of gemcitabine on malignant ascites of human pancreatic ductal carcinoma. As an in vitro assay, the human pancreatic cancer cell line (SUIT-2) was incubated in DMEM supplemented with serially diluted concentrations of gemcitabine for 24 h. The expression levels of VEGF in culture media were assayed using an enzyme-linked immunosorbent assay (ELISA). As an in vivo assay, a cell suspension (1 x 10(7) cells in 100 microliters PBS) was injected into the intraperitoneal region. The mice were randomly divided into two groups (control and treated with gemcitabine). The mice were sacrificed four weeks after inoculation, the ascites volume was measured, and the extent of peritoneal dissemination was examined. The expression levels of VEGF and CD31 in peritoneal nodules were examined by immunohistochemistry. In addition, secreted VEGF protein levels were quantified using ELISA. The results show that VEGF levels in the culture medium decreased in response to gemcitabine in a dose-dependent manner. The ascites formation and peritoneal dissemination within mice were suppressed by the treatment with gemcitabine. Immunohistochemical analysis suggested that expression of VEGF and CD31 in peritoneal nodules was suppressed by gemcitabine treatment, and the VEGF protein level in ascites was significantly decreased by gemcitabine (p<0.05). These results suggest that gemcitabine controls malignant ascites and peritoneal dissemination, either directly or indirectly, via VEGF. Moreover, intraperitoneal administration of gemcitabine may be a useful therapeutic approach for patients with malignant ascites in pancreatic carcinoma.
Kuwahara
Kenichi
K
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. tamito@hiroshima-u.ac.jp
Sasaki
Tamito
T
Kobayashi
Kensou
K
Noma
Bunjirou
B
Serikawa
Masahiro
M
Iiboshi
Tomohiro
T
Miyata
Hideki
H
Kuwada
Yukio
Y
Murakami
Masateru
M
Yamasaki
Souichirou
S
Kariya
Kenji
K
Morinaka
Kenji
K
Chayama
Kazuaki
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D001201:Ascites / Q000378:metabolism / Q000517:prevention & control*; D001202:Ascitic Fluid / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011897:Random Allocation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000093542:Gemcitabine