Establishment of combined immuno-chemotherapy with systemically administered gemcitabine and intra-portal administration of interleukin-2 in murine models of liver metastases of pancreatic cancer

Abstract

Abstract. Despite attempts to use multiple drug combinations that include gemcitabine (GEM), there is very little evidence that these combination regimens are superior to the single use of this agent. We therefore investigated the suppressive effect of the combination of systemically administered GEM and locally administered interleukin-2 (IL-2) on liver metastasis in pancreatic cancer. Tumor-bearing mice were randomly divided into four groups: a control group, an IL-2 intrasplenic (is) administration group, a GEM intraperitoneal (ip) administration group, and a GEM ip+IL-2 is group. Liver weight, liver metastases, and tumor diameter (as assessed by the Winn assay) were compared among groups. Liver weight was significantly lower in the GEM+IL-2 group than in the control and IL-2 groups. The number of liver metastases was significantly reduced in the GEM+IL-2 group compared with all other groups. Splenocyte production of interferon-γ increased significantly in the GEM+IL-2 group after stimulation with Concanavalin A. Furthermore, tumor diameter was significantly reduced in the GEM+IL-2 group in the Winn assay when compared to that of the control group. These findings suggest that a combined regimen of GEM and portally administrated IL-2 might prevent liver metastasis in pancreatic cancer patients more effectively than current approaches and could prove useful as a postsurgical adjuvant therapeutic.

Pancreatic and bile duct cancer circulating tumor cells (CTC) form immune-resistant multi-cell type clusters in the portal venous circulation

“…Previous clinical trials in Japan targeted treatment of pancreatic cancer and hepatic metastases via direct portal vein has been attempted using either perfusion of 5-Fluorouracil 19 or injection of Gemcitabine alone 20 or in mouse tumor models, Gemcitabine in combination with IL-2 as an immunostimulatory agent 21 . These small pilot studies resulted in modest extension of progression free survival but added caution due to potentially high toxicity in the case of 5-FU 19 .…”

“…These small pilot studies resulted in modest extension of progression free survival but added caution due to potentially high toxicity in the case of 5-FU 19 . The mouse model studies indicated that immune stimulation improved the effectiveness of gemcitabine not only in tumor growth suppression but also through its inhibition of MDSC suppressor function in the tumor microenvironment 21 . Our MCR culture could provide a test platform to testbed more effective immune modulation therapies directed at breaking tumor supportive immune cell-CTC interactions in the portal circulation.…”

Intravenous Administration of Dehydroxymethylepoxyquinomicin With Polymer Enhances the Inhibition of Pancreatic Carcinoma Growth in Mice

“…A luciferase expression vector (Gaussia luciferase pcDNA3) was stably transfected into AsPC-1 cells (AsPC-1-Luc) as described previously. After 1 week of acclimatization, mice underwent laparotomy involving a 2-cm horizontal incision under anesthesia with 3% isoflurane, as reported previously (23). The portal vein behind the pancreatic head was identified and exposed.…”

“…A previous study revealed that proliferation of the human pancreatic cell line BxPC-3 was blocked by administration of the proteasome inhibitor PS-341, which indirectly blocks NF-ĸB activation (21). We previously reported that DHMEQ suppressed pancreatic cell carcinoma both in vitro and in vivo using subcutaneous (8), peritoneal (22) and liver metastasis models (9,23). However, DHMEQ displays poor solubility, and it was therefore administered intraperitoneally in these previous trials.…”

Norepinephrine-induced invasion by pancreatic cancer cells is inhibited by propranolol

“…More than 90% of deaths from cancer do not result from the primary tumor, but from the development of metastases (1).…”