A control methods of postoperative tumor progression using by endotoxin cross tolerance

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 15390372
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Japanese Foundation for Cancer Research (2005); The University of Tokyo (2003-2004)
• Principal Investigator: HIKI Naoki Japanese Foundation for Cancer Research, Cancer Institute, Researcher, 癌研究所, 研究員 (30313026)
• Co-Investigator(Kenkyū-buntansha): HATAO Fumihiko The University of Tokyo, M.D., Ph.D., Associate, 医学部附属病院, 助手 (30401079) ; OGAWA Toshihisa The University of Tokyo, M.D., Ph.D., lecturer, 医学部附属病院, 講師 (80224111) ; KAMINISHI Michio The University of Tokyo, M.D., Ph.D., Professor, 医学部附属病院, 教授 (30126031)
• Project Period (FY): 2003 – 2005
• Keywords: Surgical stress / Cytokine / Melanoma / Tumor progression / Manipulation

Research Abstract

STUDY1 : The induction of resistance using synthetic LPS receptor agonist rescues fatal endotoxemia.
This study examined whether synthetic LPS receptor agonist (SLA), a nontoxic derivative of lipid A, was able to induce endotoxin tolerance (ET). METHODS : ET were induced by a daily administeration of SLA (0.02,0.2mg/kg) or LPS (0.2mg/kg) for 3days. Following 48hrs after induction, Rats were injected with LPS(25mg/rat), and the number of survival was counted during 72hrs. RESULTS : The mortality was improved by both LPS and SLA injection. CONCLUSION : The results show that SLA can induce ExT with less depression of plasma cytokines.
STUDY2 : Tumor enhancement following surgical stress is depressed by endotoxin tolerance.
Surgical stress associated with non-curative resection of tumors can aggregate primary or metastatic lesions. A possible means of repressing surgical stress is induction of endotoxin tolerance (ET). This is a state of hyporesponsiveness to endotoxin challenge that is acqui red by humans and laboratory animals following exposure to sublethal doses of endotoxin. This study examined the affect of ET on tumor growth following surgical stress. METHODS : A pilot study determined dose of Escherichia coli O111 LPS required to induce ET and number of B16 melanoma cells required to establish tumors in male C57BL/6J mice. ET was thus induced in mice by intraperitoneal administration of 1 g LPS/mouse (or distilled water for controls) twice over a 24-hour period. 48 hours after the second LPS injection, melanoma cells were administered by subcutaneous injection and surgical procedures were performed. Control animals underwent either a sham procedure (group A) or a gastrotomy closed by suture (group B), while animals with induced ET underwent a gastrotomy closed by suture (group C). Tumor size was measured for 60 postoperative days(POD). RESULTS : Tumors were firmly established by the 30th POD and differences between groups were evident by the 45th POD. On the 52nd POD, tumor sizes were 0.05 mL for A, 3.68mL for B and 0.61mL for C. The difference in tumor size for B and C was statistically significant. CONCLUSION : LPS-induced ET depresses tumor growth following surgical stress in mice.