Shoichi Kaisaki

Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis

BACKGROUND A phase II study to evaluate the efficacy and tolerability of weekly i.v. and i.p. paclitaxel (PTX) combined with S-1 was carried out in gastric cancer patients with peritoneal metastasis. PATIENTS AND METHODS Gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered i.v. at 50 mg/m(2) and i.p. at 20 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2)/day for 14 consecutive days, followed by 7 days rest. The primary end point was the 1-year overall survival (OS) rate. Secondary end points were the response rate, efficacy against malignant ascites and safety. RESULTS Forty patients were enrolled, including 21 with primary tumors with peritoneal dissemination, 13 with peritoneal recurrence and six with positive peritoneal cytology only. The median number of courses was 7 (range 1-23). The 1-year OS rate was 78% (95% confidence interval 65% to 90%). The overall response rate was 56% in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The frequent grade 3/4 toxic effects included neutropenia (38%), leukopenia (18%) and anemia (10%). CONCLUSION Combination chemotherapy of i.v. and i.p. PTX with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Vascular endothelial growth factor synthesis by human omental mesothelial cells is augmented by fibroblast growth factor-2: possible role of mesothelial cell on the development of peritoneal metastasis

Although peritoneal metastasis is an important factor determining the prognosis of patients with gastrointestinal cancer, the mechanisms have not yet been clearly defined. Human peritoneal mesothelial cells (HPMC) are the first line against disseminated tumor cells. Recent reports have shown that mesothelial cells are capable of secreting various cytokines and growth factors. In this study, we isolated human mesothelial cells from surgically resected omental tissue and examined the production and interaction of two major angiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2). Quiescent HPMC produced a considerable amount of VEGF at almost the same level as tumor cells. Interestingly, addition of FGF-2 to the culture significantly increased the mRNA synthesis and protein secretion of VEGF in a dose-dependent manner, as determined by Northern blot and ELISA. The addition of 0.5 ng/mL FGF-2 was enough to stimulate VEGF production, and the effect reached a plateau at 5 ng/mL. Reverse-transcribed polymerase chain reaction (RT-PCR) method clarified that the HPMC-derived VEGF consisted mostly of VEGF(121) and VEGF(165), which are both predominantly soluble forms. These data suggest that HPMC contribute to the development of metastases and the accumulation of malignant ascites due to the production of VEGF, especially in cancers that do not express enough amount of VEGF.

Sulforaphane induces inhibition of human umbilical vein endothelial cells proliferation by apoptosis

Sulforaphane (SUL), one of the isothiocyanates (ITCs), has recently been focused due to its inhibitory effects on tumor cell growth in vitro and in vivo, which is dependent on the direct effect on cancer cells. In the present study, we aimed to investigate the potential anti-angiogenic effect of SUL and its mechanism of action. Using the human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of SUL on the various steps of angiogenesis, including the proliferation of endothelial cells, tubular formation, and matrix metalloproteinase (MMP) production. Sulforaphane induced a dose-dependent decrease in the proliferative activity of endothelial cells, which was dependent on cell apoptosis. Also SUL inhibited tube formation on matrigel, but did not affect MMP production. The present results demonstrate the anti-angiogenic activity of SUL and its potential use as an anti-cancer drug is suggested.

Phase I Pharmacokinetic Study of Weekly Intravenous and Intraperitoneal Paclitaxel Combined with S-1 for Advanced Gastric Cancer

Objectives: 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. Patients and Methods: 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/m2, and intraperitoneally with an initial dose of 20 mg/m2, stepped up to 30 or 40 mg/m2. S-1 was administered at a fixed dose of 80 mg/m2/day for 14 consecutive days, followed by 7 days of rest. A pharmacokinetic study of PTX was also performed. Results: The MTD was determined to be 30 mg/m2, as 2 of 3 patients developed dose-limiting toxicities, grade 3 febrile neutropenia and diarrhea. Therefore, the RD was determined to be 20 mg/m2. The intraperitoneal and serum PTX concentration remained effective for over 72 and 48 h, respectively. Conclusions: 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.

Intraperitoneal administration of paclitaxel solubilized with poly(2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) for peritoneal dissemination of gastric cancer

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 phosphorylcholineand n‐butyl methacrylate, for peritoneal dissemination of gastric cancer. In a peritoneal metastasis model with transfer of MKN45P in nude mice, the effct 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 Sci 2009; 100: 1979–1985)

Spatial distribution of intraperitoneally administrated paclitaxel nanoparticles solubilized with poly (2‐methacryloxyethyl phosphorylcholine‐co n‐butyl methacrylate) in peritoneal metastatic nodules

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 Sci 2011; 102: 200–205)

Different Tissue Distribution of Paclitaxel With Intravenous and Intraperitoneal Administration

PURPOSE 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. METHODS 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. RESULT 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. CONCLUSION 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.

Selective inhibition of cyclooxygenase‐2 inhibits colon cancer cell adhesion to extracellular matrix by decreased expression of β1 integrin

High level expression of cyclooxygenase (COX)‐2 is reported in 80–90% of colorectal adenocarcinomas. In the recent years, selective inhibitors of COX‐2 have been developed, and are shown to effectively protect against cancer development and progression. Colon cancer cells, as well as the epithelial cells in general, are dependent on appropriate interactions with the extracellular matrix (ECM) proteins to achieve a number of important functions, such as proliferation, differentiation, invasion and survival. These interactions are mediated via a family of cell‐surface receptors called integrins, which interact with cytoskeletal proteins on the cytoplasmic side of the plasma membrane and thereby provide a link between the ECM and the cytoskeleton. In the present study, a high‐COX‐2 (high level COX‐2 expression) colon cancer cell line, HT‐29, and a low‐COX‐2 (low level COX‐2 expression), DLD‐1, were used to investigate the anticolon cancer effect of the selective COX‐2 inhibitor, JTE‐522. Moreover, to clarify its mechanisms of action, we focused especially on the ability to adhere to and to migrate on ECM. We could clearly demonstrate that, in addition to the decrease of the proliferative activity, JTE‐522 caused a dose‐dependent decrease in both the ability of colon cancer cells to adhere to and to migrate on ECM. These effects were, at least in part, dependent on the down‐regulation of β1‐integrin expression, which was evident in HT‐29, the high‐COX‐2 colon cancer cells, but not the low‐COX‐2, DLD‐1. In addition, prostaglandin E2 almost completely reversed the effect of JTE‐522, strongly suggesting the involvement of a COX‐2‐dependent pathway. In conclusion, for the first time, we could demonstrate the down‐regulation of β1 integrin caused by COX‐2 inhibition, with consequent impairment of the ability of cancer cells to adhere to and to migrate on ECM, which are crucial steps for cancer metastases to develop. (Cancer Sci 2005; 96: 93–99)

Vagus Nerve Preservation Selectively Restores Visceral Fat Volume in Patients with Early Gastric Cancer who Underwent Gastrectomy

BACKGROUND Body weight loss is a well-known complication after gastrectomy, and is mainly due to reduced fat volume. The effect of vagotomy on the postoperative fat volume was investigated in patients with early stage gastric cancer who underwent gastrectomy. METHODS Subcutaneous fat area (SFA) and visceral fat area (VFA) were separately measured in a computed tomographic (CT) image at the level of the umbilicus using Fat Scan software. The changes in these two fat areas were determined by comparing CT images taken before and more than 6 mo after gastrectomy, and the ratio of postoperative to preoperative fat area was calculated in 77 patients. RESULTS VFA was reduced significantly greater after total gastrectomy (TG) than distal gastrectomy (DG) (P = 0.0003). In 63 patients who underwent DG, the reduction in VFA, but not in SFA, was significantly less in vagus nerve-preserved than in vagus nerve-nonpreserved cases (59.0% ± 24.2% versus 74.9% ± 28.2%, P = 0.027). If compared in each case, VFA showed a significantly greater decrease than did SFA in vagus-nonpreserving, but not in vagus-preserving, gastrectomy (68.2% ± 37.0% versus 52.7% ± 25.2%, P < 0.0001; 76.3% ± 30.0% versus 74.9% ± 28.2%, P = 0.79). CONCLUSIONS The vagus nerve has a function to locally regulate the amount of intra-abdominal fat tissue, and selective vagotomy in gastrectomy results in a preferential reduction of visceral fat in gastrectomy. Surgical denervation of vagus may be reconsidered as a reasonable treatment for excessive obesity.

Early-outgrowth of endothelial progenitor cells can function as antigen-presenting cells

Endothelial progenitor cells (EPCs) have been recently found to exist circulating in peripheral blood of adults, and home to sites of neovascularization in peripheral tissues. They can also be differentiated from peripheral blood mononuclear cells (PBMNCs). In tumor tissues, EPCs are found in highly vascularized lesions. Few reports exist in the literature concerning the characteristics of EPCs, especially related to their surface antigen expressions, except for endothelial markers. Here, we aimed to investigate the surface expression of differentiation markers, and the functional activities of early-outgrowth of EPCs (EO-EPCs), especially focusing on their antigen-presenting ability. EO-EPCs were generated from PBMNCs, by culture in the presence of angiogenic factors. These EO-EPCs had the morphological and functional features of endothelial cells and, additionally, they shared antigen-presenting ability. They induced the proliferation of allogeneic lymphocytes in a mixed-lymphocyte reaction, and could generate cytotoxic lymphocytes, with the ability to lyze tumor cells in an antigen-specific manner. The antigen-presenting ability of EO-EPCs, however, was weaker than that of monocyte-derived dendritic cells, but stronger than peripheral blood monocytes. Since EO-EPCs play an important role in the development of tumor angiogenesis, targeting EPCs would be an effective anti-angiogenic strategy. Alternatively, due to their antigen-presenting ability, EO-EPCs can be used as the effectors of anti-tumor immunotherapy. Since they share endothelial antigens, the activation of a cellular immunity against angiogenic vessels can be expected. In conclusion, EO-EPCs should be an interesting alternative for the development of new therapeutic strategies to combat cancer, either as the effectors or as the targets of cancer immunotherapy.