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ABSTRACT: Intraperitoneal (i.p.) administration of paclitaxel nanoparticles (PTX-30W) prepared by solubulization with the amphiphilic copolymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate can efficiently suppress the growth of peritoneal metastasis. In this study, we characterized the drug distribution of i.p. injected PTX-30W in peritoneal tumor and liver in a mouse model using MKN45, human gastric cancer cells. Oregon green-conjugated PTX-30W showed perivascular accumulation in MKN45 tumor in the peritoneum at 24 h after intravenous (i.v.) injection; however, the amount of PTX in tumor was markedly less than that in liver. In contrast, a larger amount of PTX accumulated in the peripheral area of disseminated nodules at 1 h after i.p. injection and the area gradually enlarged. The depth of PTX infiltration reached 1 mm from the tumor surface at 48 h after i.p. injection, and the fluorescence intensity was markedly greater than that in liver. Interestingly, i.p. injected PTX preferentially accumulated in relatively hypovascular areas, and many tumor cells in the vicinity of PTX accumulation showed apoptosis. This unique accumulation pattern and lesser washout in hypovascular areas are thought to be attributable to the superior penetrating activity of PTX-30W, and thus, PTX-30W is considered to be highly suitable for i.p. chemotherapy for peritoneal dissemination.
Cancer Science 09/2010; 102(1):200-5. · 3.33 Impact Factor
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Joji Kitayama,
Hironori Ishigami,
Shoichi Kaisaki,
Akio Hidemura,
Masahiro Kato,
Kensuke Otani,
Takao Kamei, Daisuke Soma,
Hideyo Miyato,
Hiroharu Yamashita,
Hirokazu Nagawa
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ABSTRACT: Malignant ascites caused by gastric cancer are chemotherapy resistant and carry a poor prognosis. The efficacy of a regimen including intraperitoneal paclitaxel (PTX) was evaluated in 33 gastric cancer patients with ascetic fluid in the peritoneal cavity diagnosed with computed tomography (CT) scanning. Synchronous administration of intravenous (50 mg/m(2)) and intraperitoneal (20 mg/m(2)) PTX was performed via a subcutaneously placed intraperitoneal catheter on days 1 and 8, and S-1 was administered twice daily at 80 mg/m(2)/day for 14 consecutive days from day 1 to day 14, followed by 7 days of rest. The ascitic fluid volume was calculated with NIH Image J software using continuous CT images. After 2-4 treatment cycles, 23 (70%) patients showed reductions in their ascitic volumes of >50%. Ascites disappeared completely in 8 patients and were markedly reduced (to <3% of the original volume) in 4 of the 9 patients (44%) who initially had massive (>2,500 ml) ascites. Median overall survival was significantly better in patients with ascitic reduction. Weekly intravenous and intraperitoneal PTX combined with S-1 was highly effective in gastric cancer with malignant ascites. The change in ascitic fluid volumes determined by CT image measurements is a useful predictor of outcome in these patients.
Oncology 03/2010; 78(1):40-6. · 2.27 Impact Factor
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ABSTRACT: Adiponectin has been shown to have suppressive effects on tumor development, but the expression of adiponectin receptors in tumor tissue has not been fully elucidated. The purpose of this study was to quantitatively evaluate the expression of two adiponectin receptors, AdipoR1 and AdipoR2, in gastric cancer tissue.
The mRNA levels of AdipoR1 and AdipoR2 were evaluated by quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining in 67 gastric cancer tissues and their normal counterparts. In addition, the effects of cytokines on AdipoR1 and AdipoR2 expression in cultured gastric cancer cells were examined.
As compared to findings in the normal counterparts, AdipoR1 mRNA expression, standardized by β-actin mRNA, tended to be lower (cancer 0.488 ± 0.039, normal 0.955 ± 0.281, p = 0.0726) and AdipoR2 expression was significantly lower (0.818 ± 0.081, 1.500 ± 0.222, p = 0.0035) in gastric cancer tissue. Immunohistochemical examination showed the same tendency for AdipoR1 and AdipoR2 expression in epithelial cells. Moreover, AdipoR2 was strongly expressed in interstitial cells. However, the expression levels of these receptors did not show a strong correlation with various pathological factors. An in vitro experiment using two gastric cancer cell lines, MKN-74 and NUGC-3, showed that the expression levels of AdipoR1 and AdipoR2 were significantly decreased by transforming growth factor (TGF)-β in a dose-dependent manner.
Two major adiponectin receptors were decreased in gastric cancer as compared to findings in normal gastric epithelium. TGF-β may be involved in this receptor downregulation. This downregulation may be an ideal strategy for cancer cells to escape the antiproliferative effects of adiponectin in the initial phase of tumor development.
Journal of Gastroenterology 03/2010; 45(9):918-27. · 4.16 Impact Factor
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ABSTRACT: Intraperitoneal (i.p.) administration of paclitaxel (PTX) is a hopeful therapeutic strategy for peritoneal malignancy. Intravenously (i.v.) injected nanoparticle anticancer drugs are known to be retained in the blood stream for a long time and favorably extravasated from vessels into the interstitium of tumor tissue. In this study, we evaluated the effect of i.p. injection of PTX (PTX-30W), which was prepared by solubulization with water-soluble amphiphilic polymer composed of PMB-30W, a co-polymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate, for peritoneal dissemination of gastric cancer. In a peritoneal metastasis model with transfer of MKN45P in nude mice, the effect of i.p. administration of PTX-30W was compared with conventional PTX dissolved in Cremophor EL (PTX-Cre). The drug accumulation in peritoneal nodules was evaluated with intratumor PTX concentration and fluorescence microscopic observation. PTX-30W reduced the number of metastatic nodules and tumor volume significantly more than did conventional PTX dissolved in Cremophor EL (PTX-Cre), and prolonged the survival time (P < 0.05). PTX concentration in disseminated tumors measured by HPLC was higher in the PTX-30W than in the PTX-Cre group up to 24 h after i.p. injection. Oregon green-conjugated PTX-30W, i.p. administered, preferentially accumulated in relatively hypovascular areas in the peripheral part of disseminated nodules, which was significantly greater than the accumulation of PTX-Cre. I.p. administration of PTX-30W may be a promising strategy for peritoneal dissemination, due to its superior characteristics to accumulate in peritoneal lesions.
Cancer Science 06/2009; 100(10):1979-85. · 3.33 Impact Factor
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ABSTRACT: A dose-escalation study of weekly intraperitoneal paclitaxel (PTX) combined with S-1 and intravenous PTX was performed to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients.
Nine gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered intravenously on days 1 and 8 at a fixed dose of 50 mg/m(2), and intraperitoneally with an initial dose of 20 mg/m(2), stepped up to 30 or 40 mg/m(2). S-1 was administered at a fixed dose of 80 mg/m(2)/day for 14 consecutive days, followed by 7 days of rest. A pharmacokinetic study of PTX was also performed.
The MTD was determined to be 30 mg/m(2), as 2 of 3 patients developed dose-limiting toxicities, grade 3 febrile neutropenia and diarrhea. Therefore, the RD was determined to be 20 mg/m(2). The intraperitoneal and serum PTX concentration remained effective for over 72 and 48 h, respectively.
Combined chemotherapy of S-1 plus weekly intravenous and intraperitoneal PTX was shown to be a safe regimen that should be further explored in clinical trials.
Oncology 04/2009; 76(5):311-4. · 2.27 Impact Factor
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Jun Yamada,
Joji Kitayama,
Nelson H Tsuno,
Hiroharu Yamashita,
Hideyo Miyato, Daisuke Soma,
Kensuke Otani,
Takao Kamei,
Hironori Ishigami,
Akio Hidemura,
Shoichi Kaisaki,
Koki Takahashi,
Hirokazu Nagawa
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ABSTRACT: Intra-peritoneal administration (i.p.) of Taxanes has recently been reported to be effective for the treatment of peritoneal dissemination, presumably because extremely high concentration of the drug is achievable onto the disseminated nodules as compared to intra-venous administration. Here, we aimed to investigate the ability of non-animal stabilized hyaluronic acid (NASHA) to retain the anti-cancer drugs in the peritoneal cavity, and, consequently, improve the efficacy of i.p. administration of paclitaxel.
Mice were inoculated i.p. with MKN45P gastric cancer cells. The mice received i.p. administrations of paclitaxel, without or with NASHA, once a week for 3 consecutive weeks, and the intra-peritoneal nodules were counted after 4 weeks. The ability of NASHA to retain the i.p. administered liquid and paclitaxel in abdominal cavity was also investigated. Finally, the concentration of paclitaxel in metastatic nodule was measured with HPLC.
In the group receiving paclitaxel with NASHA, the number of disseminated nodules were significantly smaller than in those receiving paclitaxel without NASHA. The fluid volumes and concentration of paclitaxel recovered from the abdominal cavity as well as the concentrations of paclitaxel in metastatic nodule were significantly increased by the addition of NASHA.
Our results indicate that NASHA improves the exposure time of i.p. administrated paclitaxel to disseminated nodules by retaining the drug in the abdominal cavity. Since the material is used in cosmetic surgery with few adverse effects, NASHA can be clinically used as the vehicle for the i.p. administration of anti-cancer agents for advanced gastric cancer with peritoneal dissemination.
Cancer letters 10/2008; 272(2):307-15. · 4.86 Impact Factor
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ABSTRACT: Paclitaxel is considered to be suitable for disseminated cancer in the peritoneal cavity because of its high molecular weight and lipophilic characteristics. However, the difference in pharmacokinetics of paclitaxel after intraperitoneal (i.p.) and intravenous (i.v.) administration is not fully defined. Here, we investigated the tissue concentration of paclitaxel in various organs at various time points after i.p. or i.v. administration.
Paclitaxel (5 mg/kg) was administrated in an ear vein or in the abdominal cavity of rabbits. At 0.5, 6, 24, and 48 h after administration, the rabbits were sacrificed, and organs as well as peripheral blood were harvested. The serum and tissue concentrations of paclitaxel were measured by HPLC procedure.
The concentration of paclitaxel was high in the i.v. group at 0.5 h, whereas it was significantly higher in the i.p. group at 6 and 24 h. The AUC (area under the curve) was markedly higher in the omentum, mesenteric lymph nodes as well as ovary and stomach in the i.p. group.
Compared with i.v. administration, paclitaxel concentration was maintained at a high level in the whole body by i.p. administration. Repeated i.p. paclitaxel can produce more marked clinical effects than i.v. administration for metastatic lymph nodes and primary lesions as well as peritoneal dissemination.
Journal of Surgical Research 09/2008; 155(1):142-6. · 2.25 Impact Factor
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ABSTRACT: Excessive fat mass is a risk factor for postmenopausal breast cancer. Leptin, a fat cell-derived peptide hormone, elicits a growth-stimulating effect in breast cancer cells with leptin receptor expression, although the leptin-induced signal in malignant cells is not fully understood. Here, we found that exogenous leptin induced tyrosine phosphorylation of HER2 in SKBR3 cells, which showed marked overexpression of HER2. Phosphorylation of HER2 was detected at 2 min and continued up to 120 min after the start of stimulation. Leptin-induced HER2 phosphorylation was partially reduced by an epidermal growth factor receptor inhibitor, AG1478, or a Janus-activated kinase inhibitor, AG490. Leptin also induced phosphorylation of extracellular signal-regulated kinase 1/2, which was mostly abrogated by a HER2 tyrosine kinase inhibitor, AG825. In a proliferation assay, addition of 500 ng/mL leptin increased the proliferation of SKBR3, which was totally inhibited by AG825. Collectively, our data suggest that leptin can transactivate HER2 through both epidermal growth factor receptor and Janus-activated kinase 2 activation, which can cause the growth of breast cancer cells with HER2 overexpression.
Journal of Surgical Research 12/2007; 149(1):9-14. · 2.25 Impact Factor
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ABSTRACT: We assessed whether a mixture of hyaluronic acid (HA) and dye can facilitate dye-guided sentinel node (SN) mapping in gastric surgery. Although dye-guided, SN-navigated surgery is clinically applied for the treatment of early gastric cancer, there are still some practical problems. Because dyes are carried out from the SN within 20 to 30 minutes, it is sometimes difficult to detect SNs accurately, especially when they are located in a deep area in obese patients.
Patent blue or ferumoxides, superparamagnetic iron nanocolloids, with or without HA, were injected into the gastrointestinal tract of the pig, and the time course of dye transfer through the lymphatic system of the pig mesentery was assessed.
When a mixture of HA and patent blue at a volume ratio of 1:4 was injected into the submucosal layer, the time to stain the SN did not differ from that with patent blue alone; however, HA markedly prolonged the time the blue dye was retained in the SN. Patent blue alone stained the efferent lymphatics of the SN and spread to other lymph nodes within 20 minutes after submucosal injection. At the same time point, in contrast, blue stain was restricted to a part of the SN, and the efferent lymphatics were not stained for 2 hours when patent blue was mixed with HA. When a mixture of HA and ferumoxides was used as the tracer, the ferumoxides were still observed in the mesenteric SN even at 2 days after injection. Iron staining showed that Fe was trapped primarily in cells in the peripheral sinus of the SN, suggesting that the iron nanoparticles were mostly incorporated by phagocytic macrophages in the SN within a few hours.
Our data indicate that a mixture with HA prolongs the stay of a dye tracer in the SN and thus enables easy and accurate detection of the SN. HA may be a useful tool to develop a more sophisticated SN mapping technique.
Surgery 07/2007; 141(6):815-20. · 3.10 Impact Factor
