Beneficial effects of 5-Fluorouracil and heparin-based portal infusion chemotherapy combined with mitomycin C and cisplatin after curative resection of pancreatic cancer.
ABSTRACT We retrospectively assessed the benefits of 5-fluorouracil (5-FU)- and heparin-based portal infusion chemotherapy combined with systemic administration of mitomycin C (MMC) and cisplatin (CDDP) for 4 weeks following surgery (PI4W). The goal was to determine if this treatment prevented liver metastasis and improved survival for patients with potentially curative resection of pancreatic cancer.
68 patients who underwent pancreatectomy from January 1995 to August 2007 were treated. Of these cases, 22 patients received portal infusion with 5-FU (250 mg/day) for 2 weeks (PI2W) following surgery, while 25 patients received PI4W therapy (250 mg/day of 5-FU with 2,000 IU/day of heparin everyday for 4 weeks, 4 mg MMC on days 6, 13, 20, 27, and 10 mg CDDP on days 7, 14, 21, 28). The remaining 21 patients were treated without adjuvant therapy during the perioperative period.
All patients except one completed the portal infusion chemotherapy without toxicity. The cumulative liver metastasis-free survival rate in the PI4W group was significantly higher than those in the other two groups. Furthermore, in the PI4W group, 3-year survival was 91.6% and 5-year survival was 70.5%, rates which were significantly better than those observed in the other two groups.
PI4W therapy after surgery is feasible and could become a promising adjuvant therapy in patients with potentially curative resection of pancreatic cancer. and IAP.
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ABSTRACT: The polyanionic linear polysaccharide heparan sulfate specifically interacts with a multitude of extracellular ligands relevant to all steps of tumor progression. Heparan sulfate proteoglycans act as coreceptors for cytokine and chemokine signaling, modulating tumor cell growth and survival, chemotaxis, and angiogenesis. As matrix receptors, they act in concert with integrins to regulate tumor cell motility. As binding partners for matrix metalloproteinases and protease inhibitors, they regulate the proteolytic microenvironment of tumors, thus modulating metastatic spread. Processing enzymes such as heparanase and HSulf-1 and HSulf-2 can further modify the biochemical properties of heparan sulfate and promote tumor progression. As dysregulated expression of heparan sulfate proteoglycans and heparan sulfate-processing enzymes has been observed in numerous tumor entities, the development of glycan-based drugs targeting their biological functions has become an area of intense research. Promising results have been obtained both in animal models and in phase I–III clinical trials.
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ABSTRACT: Alterations in energy (glucose) metabolism are key events in the development and progression of cancer. In pancreatic adenocarcinoma (PDAC) cells, we investigated changes in glucose metabolism induced by resistance to the receptor tyrosine kinase inhibitor (RTKI) axitinib. Here, we show that human cell lines and mouse PDAC cell lines obtained from the spontaneous pancreatic cancer mouse model (Kras(G12D)Pdx1-cre) were sensitive to axitinib. The anti-proliferative effect was due to a G2/M block resulting in loss of 70-75% cell viability in the most sensitive PDAC cell line. However, a surviving sub-population showed a 2- to 3-fold increase in [C-14]deoxyglucose ([C-14]DG) uptake. This was sustained in axitinib-resistant cell lines, which were derived from parental PDAC. In addition to the axitinib-induced increase in [C-14]DG uptake, we observed a translocation of glucose transporter-1 (Glut-1) transporters from cytosolic pools to the cell surface membrane and a 2-fold increase in glycolysis rates measured by the extracellular acidification rate (ECAR). We demonstrated an axitinib-induced increase in phosphorylated Protein Kinase B (pAkt) and by blocking pAkt with a phosphatidylinositol-3 kinase (PI3K) inhibitor we reversed the Glut-1 translocation and restored sensitivity to axitinib treatment. Combination treatment with both axitinib and Akt inhibitor in parental pancreatic cell line resulted in a decrease in cell viability beyond that conferred by single therapy alone. Our study shows that PDAC resistance to axitinib results in increased glucose metabolism mediated by activated Akt. Combining axitinib and an Akt inhibitor may improve treatment in PDAC.Cell Death & Disease 04/2014; 5:e1160. DOI:10.1038/cddis.2014.125 · 5.18 Impact Factor