Combination paclitaxel and inhibitor of nuclear factor κB activation improves therapeutic outcome for model mice with peritoneal dissemination of pancreatic cancer.

Abstract

OBJECTIVES:

Paclitaxel (PTX) is a useful treatment for peritoneal dissemination of malignant tumors. However, chemoresistance due to PTX-induced nuclear factor κB (NF-κB) activation is an important cause of suboptimal therapeutic effect. We previously reported nafamostat mesilate (FUT175) inhibits NF-κB activation and promotes apoptosis in pancreatic cancer. We hypothesized that addition of FUT175 to PTX may enhance the antitumor effect in peritoneal dissemination of pancreatic cancer.

METHODS:

In vitro, we assessed NF-κB activity and apoptosis by the combination of FUT175 and PTX using human pancreatic cancer cell line (AsPc-1). In vivo, we established peritoneal dissemination in nude mice by intraperitoneal injection of AsPc-1 cells. The animals were treated with intraperitoneal injection thrice a week of FUT175, once a week of PTX, or a combination of thrice a week of FUT175 and once a week of PTX (combination group).

RESULTS:

In the combination groups, PTX-induced NF-κB activation was inhibited, and apoptosis was enhanced in comparison with other groups both in vitro and in vivo. In the combination group, tumor growth, serum tumor marker, and survival rate were significantly better than those in other groups (P < 0.05).

CONCLUSIONS:

Combination chemotherapy using PTX with FUT175 exerts an antitumor effect for peritoneal dissemination of pancreatic cancer.

• Authors: Yuki Fujiwara, Kenei Furukawa, Yohta Shimada, Tomonori Iida, Hiroaki Shiba, Tadashi Uwagawa, Takeyuki Misawa, Toya Ohashi, Katsuhiko Yanaga
• Journal: Pancreas (Pancreas) Vol. 40 Issue 4 Pg. 600-7 (May 2011) ISSN: 1536-4828 [Electronic] United States
• PMID: 21343836 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents, Phytogenic
• Benzamidines
• Guanidines
• NF-kappa B
• Caspase 8
• Paclitaxel
• nafamostat

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, pharmacology)
• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Benzamidines
• Blotting, Western
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation
• Cell Survival (drug effects)
• Drug Synergism
• Guanidines (administration & dosage, pharmacology)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (antagonists & inhibitors, metabolism)
• Paclitaxel (administration & dosage, pharmacology)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Peritoneum (drug effects, metabolism, pathology)
• Phosphorylation (drug effects)
• Treatment Outcome
• Xenograft Model Antitumor Assays