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Kiyohiko Hatake

Publications and source records attributed to Kiyohiko Hatake.

At least 19 recordsLinked to original sources
PubMed2006

M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: the critical role of the SDF-1-CXCR4 system.

OBJECTIVE: Since the macrophage colony-stimulating factor (M-CSF) has been shown to stimulate differentiation and proliferation of monocyte/macrophage lineage and to be involved in the process of neointimal formation after vascular injury, we tested the effects of M-CSF on the recruitment of bone marrow-derived progenitor cells in neointimal formation after vascular injury in mice. METHODS AND RESULTS: Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. Recombinant human M-CSF [500 microg/(kg x day)] or saline (control) was administered for 10 consecutive days, starting 4 days before the injury. Treatment with M-CSF accelerated neointimal formation in the early phase after injury, and this neointimal lesion mainly consisted of bone marrow-derived cells. M-CSF treatment had no effect on the mobilization of endothelial progenitor cells (EPCs: CD34+/Flk-1+) and reendothelialization after injury. The stromal cell-derived factor-1 (SDF-1) was markedly expressed in the neointima and media after injury, whereas CXCR4+ cells were observed in the neointima. Further, a novel CXCR4 antagonist, AMD3100, significantly attenuated the M-CSF-induced neointimal formation. CONCLUSIONS: These findings suggest that M-CSF accelerated neointimal formation after vascular injury via the SDF-1-CXCR4 system, and the inhibition of this system has therapeutic potential for the treatment of cardiovascular diseases.

Animals↗
PubMed2006

INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity.

Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wild-type but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph+ leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

A phase II Study of the global dose and schedule of capecitabine in Japanese patients with metastatic colorectal cancer.

BACKGROUND: Although the standard 3-week capecitabine regimen (1250 mg/m(2) twice daily for 2 weeks followed by a 1-week rest) has shown superior activity and improved safety over bolus 5-fluorouracil/leucovorin in two large randomized phase III trials in Europe and in the United States, only a 4-week regimen of capecitabine (828 mg/m(2) twice daily for 3 weeks) has been studied in Japan. Therefore, we performed a phase II study to investigate the 3-week regimen of capecitabine in Japanese patients with metastatic colorectal cancer (MCRC). METHODS: Previously untreated patients with MCRC received oral capecitabine 1250 mg/m(2) twice daily for 2 weeks. Treatment was repeated every 3 weeks. Blood and urine samples were collected for pharmacokinetic analysis. RESULTS: Sixty patients were enrolled. The overall response rate was 35% [95% confidence interval (CI), 23-48%], and 52% of patients had stable disease. The median time to progression was 5.5 months (95% CI, 4.2-6.7 months). The median overall survival was 20.2 months (95% CI, 16.6-27.8 months). The most frequently occurring adverse drug reaction was hand-foot syndrome (all-grade 73%; grade 3 13%). Diarrhea, anorexia, nausea and stomatitis were each seen in 37% of patients. The pharmacokinetic profiles of capecitabine and its metabolites were similar to those reported in Caucasian patients. CONCLUSIONS: The 3-week regimen of capecitabine was effective and well tolerated in Japanese patients with MCRC as well, and could be used as the basic regimen for future combination therapies.

Administration, Oral↗
PubMed2006

Anal canal carcinoma with Pagetoid spread: report of a case.

A 70-year-old man with a history of colon polyps was found to have a semipedunculated polyp in the anal canal. The patient was asymptomatic. The lesion was 14 mm in diameter and located 5 mm from the dentate line. Histological examination of biopsy specimens revealed well-differentiated adenocarcinoma of the anal canal. During transanal local excision of the tumor, an abnormality of the perianal skin was recognized. Although intraoperative frozen section of the perianal skin did not show malignancy, permanent sections of the perineal skin revealed Paget's cells in the epidermis. Pathological examination of the anal canal carcinoma revealed submucosally invasive well-differentiated adenocarcinoma with a positive distal surgical margin. Thus, we performed additional wide local excision of the perianal skin including the distal margin of the previous local excision. Pathological examination revealed continuance within the epidermis between the anal canal adenocarcinoma and Paget's cells in the perianal skin lesion. Scattered Paget's cells also formed some glandular structures. Thus, we concluded that the perianal skin lesion was Pagetoid spread of anal canal adenocarcinoma. This report shows that the perianal skin should be examined carefully in patients with anal canal carcinoma.

Adenocarcinoma↗
PubMed2006

Blockade of bulky lymphoma-associated CD55 expression by RNA interference overcomes resistance to complement-dependent cytotoxicity with rituximab.

Recently, anti-CD20 (rituximab) and anti-Her2/neu (trastuzumab) antibodies have been developed and applied to the treatment of malignant lymphoma and breast cancer, respectively. However, bulky lymphoma is known to be resistant to rituximab therapy, and this needs to be overcome. Fresh lymphoma cells were collected from 30 patients with non-Hodgkin's lymphoma, the expression of CD20 and CD55 was examined by flow cytometry, and complement-dependent cytotoxicity (CDC) assays were carried out. Susceptibility to CDC with rituximab was decreased in a tumor size-dependent manner (r=-0.895, P<0.0001), but not in a CD20-dependent manner (r=-0.076, P=0.6807) using clinical samples. One complement-inhibitory protein, CD55, contributed to bulky lymphoma-related resistance to CDC with rituximab. A decrease in susceptibility to CDC with rituximab was statistically dependent on CD55 expression (r=-0.927, P<0.0001) and the relationship between tumor size and CD55 expression showed a significant positive correlation (r=0.921, P<0.0001) using clinical samples. To overcome the resistance to rituximab by high expression of CD55 in bulky lymphoma masses, small interfering RNA (siRNA) was designed from the DNA sequence corresponding to nucleic acids 1-380 of the CD55 cDNA. Introduction of this siRNA decreased CD55 expression in the breast cancer cell line SK-BR3 and in CD20-positive cells of patients with recurrent lymphoma; resistance to CDC was also inhibited. This observation gives us a novel strategy to suppress bulky disease-related resistance to monoclonal antibody treatment.

Antibodies, Monoclonal↗
PubMed2006

Differential regulation of eotaxin-1/CCL11 and eotaxin-3/CCL26 production by the TNF-alpha and IL-4 stimulated human lung fibroblast.

Allergic asthma and allergic dermatitis are chronic inflammatory diseases and are characterized by an accumulation of eosinophils at sites of inflammation. Eotaxin-1/CCL11 and eotaxin-3/CCL26 are members of the CC chemokine family, which are known to be potent chemoattractants for eosinophils. We observed that a human lung fibroblast, HFL-1 produces eotaxin-1 and -3 in response to TNF-alpha plus IL-4 stimulation, accompanied with NF-kappaB and STAT6 activation. We explored which signaling pathways are operative in the production of eotaxin-1 and -3 using several inhibitors. Eotaxin-1/CCL11 production was inhibited by a p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, but not by the MEK (MAPK/ERK kinase) inhibitors, PD98059 and U0126. In contrast, eotaxin-3/CCL26 production was inhibited similarly by PD98059 as well as U0126 and SB203580. In addition, two proteasome inhibitors, N-acetyl-leucyl-leucyl-norleucinal (ALLN) and bortezomib with significant inhibitory activity on NF-kappaB activation, inhibited eotaxin-1/CCL11 production with IC50 8 microM for ALLN and IC50 16 nM for bortezomib. In contrast, eotaxin-3/CCL26 production was not inhibited significantly up to 10 microM of ALLN (IC50 16 microM) and up to 10 nM of bortezomib (IC50 11 nM), giving inhibition of eotaxin-3/CCL26 less sensitive than eotaxin-1/CCL11 production by the proteasome inhibitors. Synergistic inhibition was observed among lower doses of SB203580 and proteasome inhibitors, particularly in the eotaxin-1/CCL11 production. No such prominent synergism was found on the eotaxin-3/CCL26 production. The suppression of eotaxin family production by these inhibitors may be efficacious against allergic diseases.

Asthma↗
PubMed2006

High prevalence of HER-2/neu and p53 overexpression in inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Although the survival of patients with IBC has been greatly improved by the use of combined treatment modalities, women with IBC still have lower survival rates. We have summarized a single-center experience involving IBC patients. Our objectives are to clarify molecular alterations of HER-2/neu and p53 in IBC and to investigate the prognostic factors. METHODS: Between January 1990 and December 2000, 57 patients with IBC were referred to the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The incidence of IBC among primary breast cancers was 1.0% (57/5,757) in our hospital. Forty-six patients meeting Haagensen's criteria for inflammatory breast carcinoma were evaluated. All patients had biopsy-proven carcinomas but no distant metastases at referral. The median age at diagnosis for IBC was 51.8 (range, 28 to 70). All patients underwent a mastectomy. Chemotherapy was performed pre- or post-operatively. Three-year and 5-year survival rates were 56.5%, and 40.7%, respectively. Expressions of HER-2/neu and the p53 protein were determined retrospectively by immunohistochemical (IHC) staining of thin paraffin-embedded sections of primary tumors. RESULTS: Of 46 patients, 23 (50.0%) with tumors testing positive for HER-2/neu fared somewhat worse than those with negative tumors, but the differences were not significant for either overall survival (OS) or disease-free survival (DFS). Of 46 patients, 19 (41.3%) whose tumors were positive for p53 fared somewhat better than patients with negative tumors, with no significant differences in either OS or DFS. Patients presenting with less than ten pathologically involved axillary lymph nodes showed significantly better OS and DFS. CONCLUSIONS: Overexpression of HER-2/neu and the p53 protein were not significant prognostic factors in inflammatory breast cancer. However, the increased incidence of HER-2/neu and the poor outcome of IBC may be of clinical interest, suggesting the need for clinical trials of antibody therapy targeted to HER-2/neu. Moreover, a high prevalence of p53 may be useful in determining the specific use of chemotherapy.

Adenocarcinoma↗
PubMed2006

Efficacy and safety of combined trastuzumab and Paclitaxel therapy as a second-line treatment in women with metastatic breast cancer: a single institutional experience.

BACKGROUND: In breast cancer, HER-2 overexpression suggests s poor prognosis. Trastuzumab is a humanized monoclonal antibody with specificity to the HER-2 protein. We evaluated the safety and efficacy of combined trastuzumab and paclitaxel therapy in women with metastatic breast cancer. PATIENTS AND METHODS: Combination chemotherapy was given to patients with HER-2 overexpressing metastatic breast cancer. All patients had previously received one or more chemotherapy treatments. Patients received a loading trastuzumab dose of 4 mg/kg intravenously (i.v.), followed by 2 mg/kg maintenance dose at weekly intervals. A paclitaxel dose of 80 mg/m(2) was administered on the same day as the trastuzumab infusion. RESULTS: A total of 53 patients were examined. Seventy percent received two or more prior chemotherapy treatments for metastatic breast cancer, and 66.0% of patients had two or more metastatic sites. The overall response rate to our approach was 37.7%. Median time to progression was 12.0 months. Grade 3/4 neutropenia was seen in only 11.3% of patients. Peripheral neuropathy occurred in 65.1% of patients after seven treatments, requiring us to change to biweekly paclitaxel administration in 16 patients. Most of them were able to continue the treatment. Other toxicities were mild and tolerable. CONCLUSION: Combined trastuzumab and paclitaxel therapy, administered as second-line or later treatment, produced lasting objective responses and was well tolerated by women with HER-2 overexpressing metastatic breast cancer. A major obstacle to continuing treatment was peripheral neuropathy. However, modifying the interval to every 2 weeks enabled us to continue the treatment. This combination chemotherapy was safely performed in our outpatient clinic.

Antibodies, Monoclonal↗
PubMed2006

Gene therapy for breast cancer. --Review of clinical gene therapy trials for breast cancer and MDR1 gene therapy trial in Cancer Institute Hospital.

Gene therapy for advanced breast cancer is anticipated to be a useful therapeutic approach. Strategies in ongoing clinical protocols can be divided into four groups: (1) suppression of oncogenes or transfer of tumor-suppressor genes; (2) enhancement of immunological response; (3) transfer of suicide genes; (4) protection of bone marrow using drug resistance genes. We have started a clinical study of multidrug resistance (MDR1) gene therapy. Advanced breast cancer patients received high dose chemotherapy and autologous peripheral blood stem cell transplantation(PBSCT)with MDR1-transduced hematopoietic cells, and then were treated with docetaxel. Two patients have been treated so far, and in vivo enrichment of MDR1-transduced cells with docetaxel treatment has been seen. Both patients are in complete remission and had no apparent adverse effects from the MDR1 gene transfer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

[A phase-I clinical study of a combination therapy of vinorelbine and capecitabine in patients with advanced/recurrent breast cancer].

A phase-I clinical study of a combination therapy of vinorelbine and capecitabine was conducted in anthracycline- and taxane-pretreated patients with advanced/recurrent breast cancer. The objectives of this study in four medical institutions were to evaluate DLT (Dose Limiting Toxicity) and safety as primary endpoints, and tumor response and pharmacokinetics of vinorelbine as secondary endpoints. One 3-week course of treatment consisted of intravenous vinorelbine on Days 1 and 8 and oral capecitabine on Days 1 to 14, followed by a one-week rest. Vinorelbine was given at 20 mg/m(2) (Level 1) and 25 mg/m(2) (Level 2), and capecitabine was given at 1,650 mg/m(2)/day (in two divided doses, Levels 1 - 2). As the administration at each dose level in 3 patients did not cause DLT, 6 patients were additionally treated with vinorelbine at 25 mg/m(2) and capecitabine at 1,650 mg/m(2)/day (in two divided doses) to confirm safety. The major toxicities were bone marrow depression and gastrointestinal symptoms. In particular, the incidences of grade 3 or greater neutropenia (11 patients) and leukemia (10 patients) were high. They were reversible, however, and not severe enough to discontinue treatment. The response rate was 25.0% (3 PR/12). The combination with capecitabine did not affect the plasma pharmacokinetics of vinorelbine.

Aged↗
PubMed2005

Element array by scanning X-ray fluorescence microscopy after cis-diamminedichloro-platinum(II) treatment.

Minerals are important for cellular functions, such as transcription and enzyme activity, and are also involved in the metabolism of anticancer chemotherapeutic compounds. Profiling of intracellular elements in individual cells could help in understanding the mechanism of drug resistance in tumors and possibly provide a new strategy of anticancer chemotherapy. Using a recently developed technique of scanning X-ray fluorescence microscopy (SXFM), we analyzed intracellular elements after treatment with cis-diamminedichloro-platinum(II) (CDDP), a platinum-based anticancer agent. The images obtained by SXFM (element array) revealed that the average Pt content of CDDP-resistant cells was 2.6 times less than that of sensitive cells, and the zinc content was inversely correlated with the intracellular Pt content. Data suggested that Zn-related detoxification is responsible for resistance to CDDP. Of Zn-related excretion factors, glutathione was highly correlated with the amount of Zn. The combined treatment of CDDP and a Zn(II) chelator resulted in the incorporation of thrice more Pt with the concomitant down-regulation of glutathione. We propose that the generation of an element array by SXFM opens up new avenues in cancer biology and treatment.

Antineoplastic Agents↗
PubMed2005

Late phase II clinical study of vinorelbine monotherapy in advanced or recurrent breast cancer previously treated with anthracyclines and taxanes.

BACKGROUND: At present, it is one of the most important issues for the treatment of breast cancer to develop the standard therapy for patients previously treated with anthracyclines and taxanes. With the objective of determining the usefulness of vinorelbine monotherapy in patients with advanced or recurrent breast cancer after standard therapy, we evaluated the efficacy and safety of vinorelbine in patients previously treated with anthracyclines and taxanes. METHODS: Vinorelbine was administered at a dose level of 25 mg/m(2) intravenously on days 1 and 8 of a 3 week cycle. Patients were given three or more cycles in the absence of tumor progression. A maximum of nine cycles were administered. RESULTS: The response rate in 50 evaluable patients was 20.0% (10 out of 50; 95% confidence interval, 10.0-33.7%). Responders plus those who had minor response (MR) or no change (NC) accounted for 58.0% [10 partial responses (PRs) + one MR + 18 NCs out of 50]. The Kaplan-Meier estimate (50% point) of time to progression (TTP) was 115.0 days. The response rate in the visceral organs was 17.3% (nine PRs out of 52). The major toxicity was myelosuppression, which was reversible and did not require discontinuation of treatment. CONCLUSION: The results of this study show that vinorelbine monotherapy is useful in patients with advanced or recurrent breast cancer previously exposed to both anthracyclines and taxanes.

Adult↗
PubMed2005

[Induction of CPT-11 in a patient on hemodialysis with metastatic rectal cancer].

We report a case on hemodialysis with metastatic rectal cancer who was introduced to CPT-11. Although the expected pharmacokinetics was shown 24 hours post-dialysis with the infusion of dose-reduced CPT-11, grade 4 neutropenia was observed. Considering the chronic renal failure status with latent lower function of multiple organs, the dose escalation method was recommended while watching the pharmacokinetics. CPT-11 is not only the key compound for metastatic colorectal cancer, but is also effective with several other cancers. It is important for cancer patients with chronic renal failure that the feasibility and efficacy of CPT-11 should be determined by future study.

Antineoplastic Agents, Phytogenic↗
PubMed2005

[An autopsied case of metastatic endocrine carcinoma of the pancreas with primary site difficult to identify].

A 40-year-old man suffering from right cheek swelling was first diagnosed with ameloblastoma or anaplastic poorly-differentiated carcinoma of the head and neck region. He received 2 courses of CDDP/TXT chemotherapy (cisplatin 75 mg/m2, docetaxel 80 mg/m2) and achieved a partial response, but his carcinoma of the pancreas recurred. He also achieved a partial response with 2 courses of CBDCA/TXL regimen (carboplatin AUC=6, paclitaxel 200 mg/m2), but later died from his progressive disease. The autopsy revealed a pathological diagnosis of metastatic endocrine carcinoma of the pancreas. This case was close to a cancer with an unknown primary (CUP) site, and several favorable sub-sets of CUP have been identified, which are responsive to systemic chemotherapy. Poorly-differentiated neuroendocrine carcinomas like this case are highly sensitive to chemotherapy, and a careful pathological diagnosis may clarify its sensitivity to chemotherapy and the prognosis.

Adult↗
PubMed2004

Combination chemotherapy (cyclophosphamide, doxorubicin, and vincristine with continuous-infusion cisplatin and etoposide) and radiotherapy with stem cell support can be beneficial for adolescents and adults with estheisoneuroblastoma.

BACKGROUND: Adolescent-onset and adult-onset esthesioneuroblastoma is a rare disease and is considered incurable. In many patients, local resection and radiation are chosen as clinical therapy with or without chemotherapy. It was reported previously that local resection and radiotherapy led to temporary remission and, in many patients, recurrent disease. Although combination with chemotherapy has been regarded as promising, an effective regimen has not been established. In the current study, the authors investigated the effect and tolerability of the combination of chemotherapy, radiotherapy, and peripheral blood stem cell transplantation (PBSCT). METHODS: The study population included 12 patients with adolescent-onset and adult-onset esthesioneuroblastoma classified as Kadish Stage A-D. The patients received two cycles of combination chemotherapy, which consisted of cyclophosphamide, doxorubicin, and vincristine (CAD) with continuous-infusion cisplatin and etoposide (CVP). This was combined with radiotherapy with or without PBSCT. RESULTS: Nine of 12 patients (75%) obtained more than a partial response after only 2 cycles of chemotherapy. After radiation with or without PBSCT, six patients obtained a complete remission (CR). The longest survival was > 3 years. All patients who underwent PBSCT obtained a CR. The most severe side effects were loss of sodium and potassium induced by cisplatin-related renal tubular distress. Those abnormalities were temporary, and all patients recovered. CONCLUSIONS: The chemotherapy regimen with CADO and CVP does not require continuation for a long time and is very effective and tolerable for patients with adolescent-onset and adult-onset esthesioneuroblastoma. The combination with radiotherapy and PBSCT may lead to a CR without facial disfigurement. In this report, the authors discuss the feasibility and efficacy of this multidisciplinary approach.

Adolescent↗
PubMed2004

[Proteasome inhibitors].

Bortezomib, one of the proteasome inhibitors, has been approved in the United States for multiple myeloma as a second-line chemotherapy. In Japan, bortezomib has been used for for phase I clinical trials for multiple myeloma. As the action mechanism, it has been proposed that bortezomib inhibits NF-kappaB via IkappaB alpha. It also demonstrated positive results for non-Hodgkin's lymphoma and non-small cell lung cancer, but not for colorectal cancer or chronic lymphocytic leukemia. The mechanism of drug resistance has been well analized. Bortezomib is very effective but still induces adverse effects including hypotension especially when there is an overdose. Medical oncologists or hematology/oncologists must exert due caution.

Boronic Acids↗