[Consideration of preventive free-flowing IV infusion method for vinorelbine].

Vinorelbine is administered to treat solid tumors such as non-small cell lung cancer and breast cancer, and good treatment results have been reported. Although this agent is known to cause phlebitis, some studies indicated that its administration over 5 minutes or less decreased the incidence of this adverse effect to approximately 5%. However,most studies employed bolus injection, and no study has reported completing drip infusion within 5 minutes. In the present study,we investigated the preventive effects on phlebitis of administering this agent over 5 minutes or less by drip infusion,which is simpler and more useful than intravenous injection. We administered vinorelbine 35 times to 6 patients with breast cancer or non-small cell lung cancer. The mean administration period was 3 minutes and 59 seconds +/-22 seconds, and the incidence of phlebitis was 5.7%. Our administration method involving drip infusion prevented phlebitis as markedly as by intravenous injection. In addition,there were no marked differences in the incidences of adverse effects other than phlebitis. The administration method employed in this study (drip infusion within five minutes) prevented vinorelbine-induced phlebitis, and was simpler than intravenous injection.

Fas ligand expression in human pancreatic cancer.

Tumor cells escape immunologic rejection through diverse mechanisms. Fas and its ligand represent one such mechanism. Recently we reported that pancreatic cancer cell lines express Fas-ligand and kill lymphoid cells by Fas-mediated apoptosis in vitro. This study was designed to determine whether human pancreatic tumors express Fas-ligand in vivo, as a potential mediator of counterattacking the host immune cells, and to determine if Fas-ligand expression correlates with clinicopathologic characteristics and patient survival. Fas-ligand expression in 45 primary pancreatic ductal cancers and two hepatic metastases was determined using immunohistochemistry. Apoptotic cells within the tumor were assessed by immunohistochemistry for the presence of single stranded DNA. Immunohistochemistry showed that 37 (82%) of the primary tumors and both of the hepatic metastases expressed Fas-ligand. Tumor infiltrating lymphoid cells were frequently apoptotic, but the cancer cells were rarely apoptotic. Patients with Fas-ligand-positive tumor had significantly shorter survival times than Fas-ligand-negative. A multivariate analysis indicated that Fas-ligand expression and the histologic margin status were significant prognostic factors. These results suggest that the expression of Fas-ligand in human pancreatic cancers and the induction of apoptosis in the infiltrating lymphoid cells may be required to counterattack the host cytotoxic T-lymphocytic and natural killer cellular responses.

Angiotensin II activates MAP kinase and NF-kappaB through angiotensin II type I receptor in human pancreatic cancer cells.

Pancreatic ductal cancer has higher angiotensin II concentrations compared with normal pancreas or other solid tumors. This study examined angiotensin II type 1 (AT1) receptor expression and the role of angiotensin II in proliferation and survival of human pancreatic cancer cells. All three pancreatic cancer cell lines studied, from well to poorly-differentiated types, HPAF-II, AsPC-1, and Panc-1, showed strong expression of AT1 receptor. In contrast, HT-29 human colon cancer cells showed extremely weak expression. Angiotensin II stimulated the growth of pancreatic cancer cells through MAP kinase activation but had no significant effect on proliferation of HT-29 colon cancer cells. In addition, angiotensin II significantly prevented cisplatin (CDDP)-induced apoptosis through NF-kappaB activation and the subsequent production of anti-apoptotic molecules, including survivin and Bcl-XL, in pancreatic cancer cells. These findings suggest that angiotensin II plays a role in the growth and chemoresistance of AT1-positive pancreatic cancer cells through its action as a potent mitogen and anti-apoptotic molecule.

Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands inhibit the growth of PPAR-gamma expressing cancer cells through terminal differentiation. However, there are few studies examining the effect of a PPAR-gamma ligand on metastatic potential of cancer cells in an animal model and the underlying molecular mechanisms. We have recently developed a rectal cancer xenograft animal model in which anti-tumor and anti-metastatic efficacy of agents can be evaluated. This study was designed to examine whether a representative PPAR-gamma ligand, thiazolidinedione (TZD), could inhibit growth and metastasis of PPAR-gamma positive HT-29 human colon cancer cells through the induction of terminal differentiation. TZD caused G1 arrest in association with a marked increase in p21Waf-1, Drg-1, and E-cadherin expression. In untreated cancer cells, fluorescence immunostaining demonstrated beta-catenin in the nucleus and/or cytoplasm; in TZD-treated cancer cells, beta-catenin localization shifted to the plasma membrane, in association with increased E-cadherin at this site and reduced tyrosine phosphorylation of beta-catenin. In addition, TZD completely inhibited lymph node and lung metastases in the xenograft animal model, and TZD inhibited growth of primary xenografts by 40%. These results suggest that TZD can function as a cytostatic anti-cancer agent to inhibit growth and metastasis of HT-29 colon cancer cells through differentiation-promoting effects. These effects involve not only modulation of the E-cadherin/beta-catenin system, but also up-regulation of Drg-1 gene expression.

FR901228, a novel histone deacetylase inhibitor, induces cell cycle arrest and subsequent apoptosis in refractory human pancreatic cancer cells.

Histone deacetylase (HDAC) inhibitors have antiproliferative activity against human cancer cells via cell cycle arrest, differentiation, and apoptosis. However, no report has focused on the apoptotic potential of HDAC inhibitors in refractory human pancreatic cancer. This study was designed to examine the apoptotic potential of FR901228, a novel HDAC inhibitor, in five human pancreatic cancer cell lines: Capan-1, BxPC-3, HPAF, Panc-1, and MIAPaCa-2. FR901228 markedly inhibited the proliferation of all five cell lines (IC50: 1-500 nM), with the greatest effect in MIAPaCa-2 cells. Treatment of each cell line with FR901228 (10-100 nM) caused cell cycle arrest at the G1 or G2/M phase and subsequent apoptosis. FR901228 induced expression of hyperacetylated histone H3 after 3 h of treatment and overexpression of p21Waf-1 after 6 h. In addition, FR901228 induced apoptosis by activating caspase-3, which led to cleavage of p21Waf-1 into a 15-kDa breakdown product and drove cancer cells from cell cycle arrest into apoptosis. FR901228 also decreased the protein level of survivin dramatically. Our results show that FR901228 markedly inhibits the growth of pancreatic cancer cells, not only through cell cycle arrest, but also through subsequent apoptosis; this was accompanied by caspase-3 activation, survivin degradation, and p21Waf-1 cleavage. FR901228 may prove clinically useful as an agent for refractory pancreatic cancers.

Angiotensin converting enzyme-independent, local angiotensin II-generation in human pancreatic ductal cancer tissues.

Hypovascularity is an outstanding characteristic of pancreatic ductal cancer by diagnostic imaging: most pancreatic ductal cancers are hypovascular or avascular, and tumor vessels are seldom seen on angiography. However, we found that the vasculature was not always poor on angiography of surgically resected specimens of locally advanced pancreatic ductal cancers. To elucidate these controversial findings, we focused on angiotensin II, a vasoconstrictor which is directly produced from angiotensinogen at acidic pH by active trypsin. We examined whether a local angiotensin II-generating system exists in pancreatic ductal cancer tissue. We measured angiotensin II concentration and angiotensin converting enzyme (ACE) activity in tissues from normal pancreas, pancreatic ductal cancers, colon cancers, and hepatocellular carcinomas. After surgically resected specimens were homogenized, angiotensin II concentration and ACE activity in tissues were measured using the florisil method and the Kasahara method, respectively. Tissue angiotensin II levels in pancreatic ductal cancer (n=13) were significantly higher than those of normal pancreas (n=7), colon cancers (n=7), or hepatocellular carcinomas (n=7). However, there was no significant difference in the ACE activity in tissue between them. This study provides in vivo evidence of an ACE-independent, angiotensin II-generating system in pancreatic ductal cancer tissues and suggests that locally formed angiotensin II may act on the pre-existing pancreatic arteries around the tumor, leading to formation of hypovascular or avascular regions.

Protease-activated receptor-2 expression and the role of trypsin in cell proliferation in human pancreatic cancers.

Protease-activated receptor (PAR)-2 is a G protein-coupled receptor that is activated by trypsin. The purpose of this study was to examine PAR-2 expression and the role of trypsin in cell proliferation in human pancreatic cancer cells. All four pancreatic cancer cell lines studied, from well to undifferentiated types, AsPC-1, BxPC-3, Panc-1, and MIAPaCa-2, had significant levels of PAR-2 mRNA detected by reverse transcription-polymerase chain reaction, and showed a band of about 55 kDa corresponding to the known molecular weight of PAR-2: AsPC-1, BxPC-3 and Panc-1 showed a strong band, and MIAPaCa-2 showed a weak one. Immunocytochemically, AsPC-1, BxPC-3, and Panc-1 showed intense immunostaining for PAR-2, predominantly in the plasma membrane, while in MIAPaCa-2, immunostaining was weak. Proliferative activity of AsPC-1 cells was increased by concentrations of trypsin as low as 10 nM, and activity peaked at a concentration of 100 nM, representing almost 60% of that induced by 10% fetal bovine serum. In contrast, trypsin had no significant effect on proliferation of MIAPaCa-2 cells. These findings suggest that trypsin plays a role in the growth of PAR-2-positive pancreatic cancer cells and serves as a potent mitogen in vitro, functioning as a growth factor.

Sentinel lymph node navigation surgery for pancreatic head cancers.

Recently, sentinel lymph node (SN) concept has been validated for gastrointestinal and breast cancers. Our previous study has shown that the No. 13 posterior pancreaticoduodenal lymph node group constitutes the major regional drainage site from primary tumors in the pancreatic head, and that the status of these nodes predicts that of the No. 16 abdominal paraaortic lymph node group. Based on these results, we have developed SN navigation surgery for pancreatic cancer, in the search for more curable and less invasive surgery. In brief, 2% patent blue dye is injected into the peritumoral area. Approximately 5 min later, one or more blue-stained nodes within the area of the No. 13 lymph node group are identified and excised for intraoperative frozen section examination. The subsequent surgical decision-tree is as follows: i) if No. 13 SNs are negative, an extended No. 16 lymph node dissection is not performed to reduce morbidity, and ii) when cancer is found, the No. 16 lymph nodes are dissected completely. Since July 1997, nine of 21 patients scheduled to undergo an extended curative surgery underwent SN biopsy. SNs within the area of the No. 13 lymph node group were identified in 8 (89%) patients. An extended No. 16 lymph node dissection was avoided in 4 SN-negative patients. The overall 3-year survival rate of the 21 patients was 36%, and 4 patients (three SN-negative and one SN-positive patients) with stage IVa disease were alive 3 years after surgery. Three SN-negative patients underwent an extended curative pylorus-preserving pancreaticoduodenectomy (PpPD) with combined portal vein resection, but without an extended No. 16 dissection. In conclusion, SN biopsy and curative PpPD can increase curability, reduce morbidity, and provide long-term survival in patients with locally advanced pancreatic head cancer as an alternative to routine extended No. 16 lymph node dissection.

Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, modulates the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3.

Activation of peroxisome proliferator-activated receptor (PPAR)-gamma induces terminal differentiation and growth inhibition associated with G1 cell cycle arrest in some cancer cells. The multifunctional molecule beta-catenin performs important roles in intercellular adhesion and signal transduction. However, no report has focused on actions of PPAR-gamma in regulating the E-cadherin/beta-catenin system. We examined whether thiazolidinedione (TZD), a potent PPAR-gamma ligand, could modulate the E-cadherin/beta-catenin system in a human pancreatic cancer cell line, BxPC-3, that has been found to express PPAR-gamma. According to Western blotting, TZD markedly increased differentiation markers including E-cadherin and carcinoembryonic antigen, while beta-catenin did not change significantly. In untreated cells, fluorescence immunostaining demonstrated beta-catenin predominantly in the cytoplasm and/or nucleus; in TZD-treated cells, beta-catenin localization had dramatically shifted to the plasma membrane, in association with increased E-cadherin at this site. Thus, a PPAR-gamma ligand appears to participate not only in induction of differentiation in pancreatic cancer cells, but also in the regulation of the E-cadherin/beta-catenin system. Such ligands may prove clinically useful as cytostatic anticancer agents.