Shunsuke Yanoma

Plasma concentrations of VEGF and bFGF in patients with gastric carcinoma

We examined plasma levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in 54 patients with gastric carcinoma. Postoperative survival was significantly poorer in patients with plasma VEGF levels more than 10.0 pg/ml at the time of surgery. By an univariate analysis of the factors affecting survival, serosal invasion, lymph node metastasis, peritoneal dissemination, lymphatic vessel invasion, curability, and VEGF proteins were significant. By a multivariate analysis only VEGF levels and curability remained significant. Patients with recurrent disease, including liver metastasis, had significantly higher plasma VEGF concentrations than those with resectable primary tumors. VEGF, not bFGF, may serve as an independent prognosticator and a sensitive indicator for liver recurrence in patients with gastric carcinoma.

The F(ab')2 fragment of an Aβ-specific monoclonal antibody reduces Aβ deposits in the brain

Abstract This work examines whether administering the F(ab´) 2 fragment of an IgG1 monoclonal antibody (mAb) targeting the N-terminal 1–13 amino acids of the β-amyloid peptide (Aβ mAb) reduces amyloid deposition in Alzheimers disease (AD). The F(ab′) 2 fragment was injected intraperitoneally or intracranially into Tg2576 mice, a murine model of human AD. Both routes of administration significantly reduced Aβ plaque formation in the brain, as determined immunohistochemically and by monitoring levels of Aβ 1–40 and Aβ 1–42 peptide. Use of the F(ab′) 2 fragment significantly reduced phagocytic infiltration in the CNS when compared to intact mAb. Since IgG1 Abs do not fix complement, these findings suggest that effective in vivo clearance of amyloid deposits can be achieved without stimulation of FcR-reactive phagocytes or activation of the complement cascade.

Reduction of in vivo tumor growth by MMI-166, a selective matrix metalloproteinase inhibitor, through inhibition of tumor angiogenesis in squamous cell carcinoma cell lines of head and neck

Matrix metalloproteinases (MMPs) have been implicated in tumor invasion, metastasis, and angiogenesis. We have recently shown that MMI-166, a new orally active MMP inhibitor specific for MMP-2 and -9, suppressed experimental metastasis of Lewis lung cancer, C-H1 human colon cancer, and pancreatic cancer without affecting tumor growth in vitro. In the present study, we determined whether oral administration of MMI-166 reduces tumor growth not only in such tumors but also in squamous cell carcinoma of head and neck (SCCHN). MMI-166 inhibited both activity of MMP-2 and -9 without affecting steady state levels of their mRNAs in SCCHN. Interestingly, protein levels of MMP-2 and -9 from the cultures were drastically diminished by culturing with MMI-166. This was also observed in xenografts of MMI-166-administered mice. In addition, daily oral administration of MMI-166 (100mg/kg) inhibited local tumor growth accompanied by the reduction of blood vessel density and Ki-67-positivity and increase in terminal deoxynucleotidyl transferase-mediated cUDP nick-end labeling (TUNEL)-positivity. These results suggested that orally administered MMI-166 reduced in vivo tumor growth of SCCHN through inhibition of angiogenesis and induction of apoptosis accompanied by the reduction of MMP productions and activities. Therefore, MMI-166 seems to be useful for tumor dormancy therapy of SCCHN.

Prognostic value of tissue inhibitor of matrix metalloproteinase-1 in plasma of patients with gastric cancer

Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in plasma has been reported to be related to disease progression in patients with gastric cancer. However, the prognostic significance of plasma TIMP-1 concentrations has not been clarified. Concentrations of TIMP-1 protein were measured by enzyme-linked immuno-sorbent assay in plasma samples of 147 preoperative patients who subsequently underwent gastric resection, and prognosis was compared. The cut-off value of plasma TIMP-1 concentrations was defined as 112.5 ng/ml, referring to the TIMP-1 levels in patients with intramucosal gastric cancer. Twenty-nine out of 147 patients had higher plasma TIMP-1 levels than the cut off value. When the patients were divided into those with elevated values and those with normal TIMP-1, such parameters as age, serosal invasion, metastases to lymph nodes, peritoneum, and liver, lymphatic invasion, curability, and stage were significantly different between the two. By univariate analysis of the factors affecting survival, macroscopic type, histology, serosal invasion, metastasis to lymph node, peritoneum, and liver, vessel invasions, curability, and plasma TIMP-1 were significant. However, multivariate analysis revealed that TIMP-1 was the only significant factor. In patients with gastric cancer, plasma TIMP-1 seem to be an independent and most powerful prognosticator for the survival.

Suppressed cellular immunity in patients with nasopharyngeal carcinoma

The subsets and functions of lymphocytes were investigated in patients with nasopharyngeal carcinoma (NPC). The patients were divided into two groups comprising tumor-bearing patients and those in remission. There was no difference in the proportion of T cells among tumor-bearing, remission and healthy control groups. The percentages of inducer/helper T cells and natural killer cells were smaller in the tumor-bearing group than in the control group whereas the percentage of suppressor T cells was greater in the tumor-bearing group. Phytohemagglutinin-stimulated blastogenesis was markedly suppressed in the tumor-bearing group. The responsiveness to interleukin-2 of blastogenesis and of natural killer and lymphokine-activated killer activities was lowered in the tumor-bearing group. These parameters in the remission group were intermediate between those of the tumor-bearing and control groups. These results suggest that cellular immunity is suppressed in patients with NPC and that the suppressed condition still remains even in remission. Immunotherapy is considered to be indispensable for the proper treatment of NPC.

Therapeutic efficiency of IL-2 gene transduced tumor vaccine for head and neck carcinoma.

Transduction of the human interleukin-2 (IL-2) gene into tumor cells was carried out in order to develop a new immunotherapy for advanced head and neck carcinomas with a poor outcome. We transduced the IL-2 gene into KB cells, a head and neck squamous cell carcinoma cell line, using a defective herpes simplex viral (HSV) amplicon vector as a gene transfer vehicle. A high level of IL-2 was secreted by IL-2 gene-transduced KB cells (KB/IL-2). The IL-2 producibility of irradiated KB/IL-2 cells was almost the same as that of non-irradiated cells. In the tumor establishment model in nude mice, IL-2 and interferon-gamma (IFN-gamma) at high concentrations were detected in the sera of mice transplanted with KB/IL-2 cells. The spleen cells of nude mice transplanted with KB/IL-2 cells exhibited high cytotoxic activity compared to those from mice transplanted with KB cells and from untreated mice. Three of five mice transplanted with KB/IL-2 cells rejected tumors. In the treatment of established tumors, therapeutic effects due to irradiated KB/IL-2 were dose-dependent. The suppressive effects on tumor growth were blocked by anti-asialo GM1, anti-human IL-2 and anti-IFN-gamma antibodies. Immunohistochemical observation revealed the presence of asialo GM1(+) cells among the KB/IL-2 cells in tumors transplanted into nude mice.

Molecular analyses of cell origin and detection of circulating tumor cells in the peripheral blood in alveolar soft part sarcoma

Alveolar soft part sarcoma (ASPS) is a distinct, rare soft tissue tumor with an unknown histogenesis and a tendency for late widespread metastases to lung, bone, and brain. It is now clear that they are caused by a specific unbalanced translocation, der(17)t(X;17)(p11;q25), which results in the formation of an ASPSCR1-TFE3 (alias ASPL-TFE3) fusion gene. The rearrangement results in the expression of chimeric transcripts, which can be identified by means of reverse transcriptase-polymerase chain reaction (RT-PCR). We investigated the histogenesis of ASPS and attempted to detect circulating ASPS tumor cells in peripheral blood. The immunohistochemical and genetic details of four cases and one cell line of ASPS were examined. An immunohistochemical analysis and RT-PCR did not detect myogenic differentiation gene MYOD1. The sensitivity of nested RT-PCR for detection of circulating ASPS cells was assessed by demonstrating that the tumor cell-associated gene translocation could be detected in 50 tumor cells/2 mL of blood. Clinically, it was detectable in a peripheral blood sample (2 mL) of ASPS patient with distant metastases. The findings suggest that ASPS is not of skeletal muscle origin. ASPS tumor cells in the peripheral blood could be monitored by RT-PCR.

Intratumoral concentrations of tissue inhibitor of matrix metalloproteinase 1 in patients with gastric carcinoma

Previously, the authors clarified that the plasma concentration of tissue inhibitor of matrix metalloproteinase 1 (TIMP‐1) in patients with gastric carcinoma was a significant predictor of tumor invasiveness and metastasis.

An Experimental Model of Tumor Dormancy Therapy for Advanced Head and Neck Carcinoma

An experimental model of tumor dormancy therapy for advanced head and neck carcinoma was developed. After transplantation of KB cells into nude mice, the mice were given tiracoxib, a selective cyclooxygenase (COX)‐2 inhibitor, probucol, an antioxidant, and S‐1, an oral pro‐drug of 5‐fluorouracil (5‐FU), or combinations of two of them. The combined administration of tiracoxib with probucol significantly inhibited the tumor growth. The angiogenesis in this group was markedly reduced. Tiracoxib and probucol did not affect the intratumoral concentration of 5‐FU when coadministered with S‐1. The combined use of tiracoxib and probucol is thus a candidate for use in maintenance therapy after the primary therapy for patients with advanced head and neck carcinoma.

Production of granulocyte colony-stimulating factor by head and neck carcinomas

Detectable levels of G-CSF by enzyme-linked immunosorbent assay (ELISA) were found in sera of 4 out of 15 patients with head and neck carcinomas. Also cells prepared from the tumors of these 4 patients secreted G-CSF. The supernatants of cells derived from all 15 patients did not contain granulocyte-monocyte CSF, monocyte CSF, tumor necrosis factor-α, transforming growth factor-β1, epidermal growth factor, interleukin (IL)-1β and IL-6. These findings suggest that leukocytosis in patients with carcinomas might be due to the production of G-CSF by tumor cells.