Biomedical subjects

Yoshihide Otani

Publications and source records attributed to Yoshihide Otani.

58 records · Page 4Linked to original sources

PubMedDate not supplied

Tyrosine kinase inhibitor SU6668 inhibits peritoneal dissemination of gastric cancer via suppression of tumor angiogenesis.

BACKGROUND: Peritoneal dissemination of cancer involves several steps, including tumor cell attachment, invasion and growth in the peritoneum. Tumor angiogenesis is a prerequisite for the growth of disseminated tumor. Vascular endothelial growth factor (VEGF) and its receptor are major regulators of angiogenesis. PURPOSE: We examined the cytotoxic effects of SU6668, an inhibitor of VEGF tyrosine kinase receptors, on in vitro gastric cancer cell lines and human umbilical vascular endothelial cells (HUVEC); we also examined the antitumor effects of SU6668 on human gastric cancer cells administered intraperitoneally into nude mice. MATERIALS AND METHODS: Direct cytotoxicity to gastric cancer cells (TMK-1, MKN-45 and MKN-74) and normal cells (HUVEC) was determined by the MTT assay and the bromodeoxyuridine (BrdU) incorporation assay, with and without VEGF-evoked growth stimulation in vitro. TMK-1 cells were transplanted intraperitoneally into nude mice, followed by twice daily oral administration of SU6668 (200 mg/kg/day) for two weeks starting on the first day after transplantation. Both the number and the wet weight of disseminated peritoneal tumor nodules were assessed. RESULTS: In the MTT assay, SU6668 demonstrated low-grade cytotoxicity to the cell growth of three gastric cancer cells, with a 50% inhibitory concentration (IC50) of 22.6 microg/ml for TMK-1, 31.8 microg/ml for MKN-45 and 26.7 microg/ml for MKN-74; HUVEC was sensitive to SU6668 with an IC50 of 8.9 microg/ml. In the BrdU assay, VEGF stimulated DNA synthesis in HUVEC, while the incorporation of BrdU was not affected by VEGF in gastric cancer cell lines. SU6668 inhibited VEGF-induced DNA synthesis in HUVEC, while BrdU incorporation of gastric cancer cell lines was inhibited by SU6668 without correlation to VEGF stimulation. Peritoneal dissemination of cancer in nude mice was significantly suppressed by SU6668 compared with a control group at the p<0.05 level. CONCLUSION: The mechanism of the antitumor activity of SU6668 may not involve direct toxicity to cancer cells, but may rather be an inhibitory effect on tumor angiogenesis, resulting in the inhibition of tumor dissemination in the peritoneum.

Adult↗

PubMedDate not supplied

A novel human monoclonal antibody derived from tumor-infiltrating lymphocytes in lung cancer inhibits cancer cell growth with morphological changes.

Tumor-infiltrating lymphocytes (TIL) were isolated from surgically resected human samples using hybridoma techniques, and human monoclonal antibodies (HuMoAbs) were produced. Stable antibody-producing hybridoma cell lines were established and, on the basis of reactivity to human cancer cell lines, a clone of HuMoAb, named HoAKs-1, was selected. By confocal microscopy, we confirmed that HoAKs-1 showed specific and intense reactivity to the cell membrane of HLC-1 and PANC-1, wheareas the antibody did not show reactivity to human umbilical vein endothelial cells (HUVECs). Using xenografts formed from epithelial cancer cell lines in nude mice, we also demonstrated a broad spectrum of reactivity of the antibody in 6 out of 14 xenografts. In addition, using surgically resected clinical specimens from two patients with lung cancer, we showed that HoAKs-1 had specific reactivity to cancerous lesions but not to normal sites. In an in vitro experiment, HoAKs-1 induced morphological changes with neurite-like cytoplasmic processes in MKN-45, HLC-1 and PANC-1, whereas no morphological alterations were observed in HUVECs. Growth inhibition rates by HoAKs-1 were 63% in HLC-1 and 47% in MKN-45, while no growth inhibition occurred in normal HUVECs. We confirmed that HoAKs-1 recognized a 55 kDa protein by determining the molecular weight of the HoAKs-1 reacting protein. In conclusion, we successfully produced a novel HuMoAb, HoAKs-1, which reacted specifically to cancer cells and inhibited cell growth with morphological changes. HoAKs-1 may have the potential to be utilized as an anticancer agent, without causing any immunological reaction in humans.

Animals↗

PubMedDate not supplied

Role of the MTT chemosensitivity test in the prognosis of gastric cancer patients after postoperative adjuvant chemotherapy.

The clinical usefulness of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) chemosensitivity test (MTT assay; MTTA) in the selection of anticancer drugs against advanced gastric cancer (AGC) was evaluated. MTTA is widely used to predict patient responses to particular drugs, allowing for the selection of appropriate chemotherapeutic drugs and the avoidance of ineffective chemotherapeutic drugs, thereby improving patient survival. Since 1989, we have accumulated MTTA efficacy data from AGC patients. In this study, the present clinical roles of MTTA and the data from 202 patients with stage III or IV gastric cancer analyzed for survival outcome following surgery, with or without postoperative chemotherapy, evaluated by MTTA, are discussed. The patients were divided into 3 groups; an adapted group found to be sensitive to chemotherapy by MTTA, a non-adapted group found to be insensitive to chemotherapy by MTTA and a group that received no chemotherapy. For stage III gastric cancer patients, the adapted group had a statistically better survival rate compared to the other groups, while for stage IV patients, there was no difference in survival rate between any of the groups. However, further classification of stage IV patients as to the presence or absence of peritoneal dissemination (P) showed that the adapted group with P showed better prognoses than the other groups with P. The analysis of data collected since 2000 revealed that the 11 patients in the taxane-adapted group, who received chemotherapeutic regimens that included taxanes and were found to be sensitive to taxanes by MTTA, demonstrated better survival than the taxane non-adapted group (n=11) (p=0.045). In conclusion, MTTA results predicted patient prognoses, based on the selection of appropriate chemotherapy.

Adult↗

PubMedDate not supplied

A pilot study of combination chemotherapy with S-1 and low-dose cisplatin for highly advanced gastric cancer.

BACKGROUND: The surgical outcome for advanced gastric cancer, even following curative surgery, is associated with a poor prognosis. A pilot study in advanced gastric cancer patients was carried out using pre-operative chemotherapy with S-1 and low-dose cisplatin (CDDP) (TSLD). PATIENTS AND METHODS: Twenty-one patients with stage IV gastric cancer were treated with TSLD as the initial treatment, after informed consent had been obtained. Surgery was performed when curative resection was deemed feasible in selected patients who showed improvement in their tumors. Other regimens including CPT-11 or taxanes were utilized as second-line chemotherapy when the tumor showed no change or progressive disease following TSLD therapy. RESULTS: No patient had a complete response, while 11 had partial responses following TSLD therapy, yielding an overall response rate of 52.4%. Fifteen out of 21 (71.4%) underwent surgery following TSLD therapy, while curative surgery determined by histological investigation was performed in 10 out of 15 (47.6%) patients. No grade 4 toxicities or treatment-related deaths were observed. The following grade 3 toxicities were observed: neutropenia (6 patients), thrombocytopenia (1 patient) and anemia (1 patient). The other toxicities observed, including gastrointestinal toxicity, were grade 2 or less. The median survival time of all patients was 526 days, and 1- and 2-year survival rates were 64.9% and 41.7%, respectively. CONCLUSION: TSLD is a potent regimen with a low toxicity profile for highly advanced gastric cancer.

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