Biomedical subjects

Masahiko Miura

Publications and source records attributed to Masahiko Miura.

18 recordsLinked to original sources

PubMed2007

Sulfoglycolipids as candidate antiangiogenic radiosensitizers.

Angiogenesis is considered an essential process for the growth of solid tumors and, accordingly, angiogenesis has been a focus of attention for cancer therapy. Although various antiangiogenic agents have been developed, adverse effects and limitations associated with antitumor therapies have recently become apparent. To overcome these problems, combining such agents with chemotherapy or radiotherapy is now strongly recommended in clinical practice. Provided such combination treatment, from the onset of therapy, different strategies in developing antiangiogenic agents should be used to enhance any combinatory effects and reduce adverse effects. By applying the concept of radiosensitizers, a new class of antiangiogenic treatments should now be possible. We recently developed sulfoglycolipids that possess such properties. In this review, we discuss the properties of antiangiogenic radiosensitizers and their potential usefulness.

Angiogenesis Inhibitors↗

PubMed2006

Brachytherapy of stage II mobile tongue carcinoma. Prediction of local control and QOL.

BACKGROUND: There is no consensus as to the prognostic model for brachytherapy of tongue carcinoma. This study was designed to evaluate the prognostic factors for local control based on a large population under a unified treatment policy. RESULTS: Between 1970 and 1998, 433 patients with stage II tongue squamous cell carcinoma were treated by low-dose-rate brachytherapy. This series included 277 patients treated with a linear source with a minimum follow-up of 3 years. A spacer was introduced in 1987. The primary local control rates were 85.6%. CONCLUSION: In the multivariate analysis, an invasive growth pattern was a significant factor for local recurrence. The disease-related survival was influenced by old age and an invasive growth pattern. A spacer lowered mandibular bone complications. The growth pattern was the most important factor for recurrence. Brachytherapy was associated with a high cure rate and the use of spacers brought about good quality of life (QOL).

Adult↗

PubMed2006

Alpha-sulfoquinovosylmonoacylglycerol is a novel potent radiosensitizer targeting tumor angiogenesis.

Angiogenesis is a promising target for the treatment of cancer, and varying types of antiangiogenic agents have been developed. However, limitations and problems associated with antiangiogenic therapy have recently arisen. Although radiotherapy can be combined with antiangiogenic compounds to overcome these difficulties, almost all previously described angiogenesis inhibitors could still cause side effects at effective doses, and only additive effects are seen in current combination therapy. In this study, we identified a member of the sulfoquinovosylacylglycerols, alpha-sulfoquinovosylmonoacylglycerol (alpha-SQMG), originally derived from sea urchins, as a potent radiosensitizer. The agent synergistically inhibits angiogenesis at low doses when combined with ionizing radiation. Combined treatment with alpha-SQMG and radiation seems to promote the adoption of a senescence-like phenotype by vascular endothelial cells. Finally, the agent remarkably enhances the radioresponse of human tumors transplanted into nude mice, accompanied by a significant reduction in the vascularity of the tumors. Collectively, alpha-SQMG may be a novel potent radiosensitizer targeting angiogenesis.

Angiogenesis Inhibitors↗

PubMed2006

In-vivo visualization of radiation-induced apoptosis using (125)I-annexin V.

BACKGROUND: As apoptosis occurs in tumors within a short time after irradiation, the detection of the frequency of apoptosis may be useful as an indicator of the effect of treatment. For the evaluation of apoptosis under these conditions, tissue extraction from patients is indispensable. AIM: To develop a noninvasive imaging technique to measure and monitor apoptosis in tumor cells caused by X-irradiation using (125)I-radiolabeled annexin V. METHODS: The tumors used were human ependymoblastomas, which were transplanted into nude mice. The tumors were irradiated at 2, 5 or 10 Gy. (125)I-annexin V was administered intravenously 6 h after irradiation. In the 5 Gy irradiation group, the isotope was injected at various time intervals (3, 6 and 12 h) after irradiation. Three hours after the injection, the mice were sacrificed, the tumors were quickly removed and frozen sections were prepared at 6 and 40 microm thickness using a cryomicrotome. In autoradiographic imaging, the tumor-to-muscle ratios were compared in the respective irradiated groups. In addition, apoptosis detection by the in-situ end-labeling (Klenow) assay was conducted on the same sections. The number of Klenow-positive cells was counted in 100 x fields for each section. RESULTS: Both autoradiography and immunohistochemical staining showed a significantly higher frequency of apoptosis in the neoplasms in all irradiated groups than in the control group (P<0.05). Although immunohistochemical staining revealed a peak apoptosis frequency in the 5 Gy irradiated group, autoradiography revealed a peak in the group receiving a lower dose than 5 Gy. When the time from irradiation to annexin injection was varied, both imaging methods showed a peak apoptosis frequency in the group receiving the injection 6 h after irradiation. CONCLUSION: It is possible to predict the effect of treatment in cancer in a noninvasive manner by apoptosis imaging in vivo after radiotherapy.

Animals↗

PubMed2005

Heat shock induces phosphorylation of histone H2AX in mammalian cells.

Heat shock induces a variety of biological events including gene activation, cell cycle arrest, and apoptosis. Heat shock has recently been shown to be potentially useful when combined with radiation in cancer therapy, probably because, in mammalian cells, heat inhibits the repair of double-strand breaks (DSBs) induced by ionizing radiation. It remains unclear, however, whether heat shock by itself induces DSBs. In this communication, we present the first evidence that heat shock induces the phosphorylated form of histone H2AX, which is thought to be generated at the chromatin proximal to DSB sites. These results suggest that heat shock induces DSBs in mammalian cells and may provide direct evidence to explain previous reports on DSB-related events occurring after heat shock treatment.

Animals↗

PubMed2005

Interstitial brachytherapy and neck dissection for Stage III squamous cell carcinoma of the mobile tongue.

The purpose of this study is to describe the cause-specific survival rate, local control rate, salvage rate of neck metastasis, and post-treatment eating and speaking conditions for stage III mobile tongue squamous cell carcinomas and its subgroups. Between 1968 and 1999, 117 previously untreated patients with stage III mobile tongue carcinomas underwent mainly brachytherapy with external beam irradiation (EBRT) and neck dissection. A multivariate analysis was performed for the cause-specific survival rate on the various factors. The 1-, 3- and 5-year cause-specific survival rates for all patients were 76%, 54% and 54%, respectively. The 1-, 3- and 5-year primary control rates for all patients were 67.6%, 63.4% and 59.2%, respectively. There were statistically significant differences in cause-specific survival rates among stage III subgroups of T3N0, T1-2N1 and T3N1 (p = 0.0002). Our treatment method for patients with stage III mobile tongue squamous cell carcinoma was effective and acceptable.

Adult↗

PubMed2004

Evidence that basal activity, but not transactivation, of the epidermal growth factor receptor tyrosine kinase is required for insulin-like growth factor I-induced activation of extracellular signal-regulated kinase in oral carcinoma cells.

IGF-I receptor (IGF-IR) is involved in numerous biological functions via its major downstream signaling molecules, extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase/Akt. The IGF-I-induced activation of ERK, but not that of Akt, is reportedly mediated by the transactivation of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK). The mechanism for the EGFR-TK-dependent activation, however, still remains largely unknown. We found that an oral carcinoma cell line overexpressing EGFR, Ca9-22, exhibited IGF-I-induced activation of both Akt and ERK, but that only the latter was significantly decreased by a specific inhibitor of EGFR-TK, tyrphostin AG1478. In this report we provide evidence for the existence in this cell line of a novel mechanism by which IGF-I induces ERK activation in a manner that is dependent on the basal level of EGFR-TK activity, but is independent of receptor transactivation. In addition, we show that c-Raf kinase is likely to be a key regulator of this mechanism. The elucidation of such a unique mechanism involving cross-talk between EGFR and heterologous receptors may shed additional light on the clinical use of EGFR-TK inhibitors in antitumor therapies.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Determination of the depth of 50% of maximum ionization, I50, for electron beams by the divided difference method.

A new characterization of depth-ionization parameters for electron beams is empirically deduced from our data analysis based on the divided difference method (the DD method), which employs the numerical differential of an ionization curve. The important feature of the present method is that it does not necessarily require normalized percent depth-ionization (NPDI) data. The depth of 50% of maximum ionization, I50, which is an important parameter for electron beam dosimetry, can be deduced from the analysis of an unnormalized (or partial) depth-ionization (UDI) curve obtained over a short interval of depth. The values of I50 determined by the DD method are in agreement to within 0.1 mm for energies of 4, 6, and 9 MeV, compared with the ones determined by the TG-51 protocol method (or the conventional method), and the difference was 0.9 mm for 12 and 15 MeV. The dose at the reference depth, dref, calculated from I50 by the DD method, is found to be in agreement with TG-51 to within 0.1%. The field size dependence of the DD method using UDI data was studied for three field sizes: 6 x 6, 10 x 10, and 20 x 20 cm2. For all energies, the discrepancies of I50 as determined by both methods were 0.9 mm on average for the 6 x 6 cm2 fields and 0.6 mm for the other two field sizes. This dependence was remarkable for 6 x 6 cm2 fields for 12 and 15 MeV, and the discrepancies shown by the DD method were 1.2 mm for 12 MeV and 1.8 mm for 15 MeV, respectively. Since the reference field size in clinical dosimetry is usually 10 x 10 cm2, this dependence will not affect clinical dosimetry. The DD method could be an alternative option for checking beam quality in dose calibration.

Algorithms↗

PubMed2004

Insulin-like growth factor I receptor does not contribute to heat shock-induced Activation of Akt and extracellular signal-regulated kinase (ERK) in mouse embryo fibroblasts.

We have investigated the role of insulin-like growth factor I receptor (IGF-IR) in heat shock-induced activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 ' kinase (PI3-K) pathways. We utilized mouse embryo fibroblasts (MEFs) devoid of endogenous IGF-IR (R-) and MEFs overexpressing human IGF-IR (WT) and examined the activation kinetics of extracellular signal-regulated kinase (ERK) and Akt following heat shock treatment. There were no differences in the kinetics or temperature dependence of activation of either ERK or Akt between the cell lines. As expected, heat shock failed to induce autophosphorylation of IGF-IR overexpressed in WT cells. Surprisingly, the autophosphorylation of endogenous epidermal growth factor receptor (EGFR), which is thought to play an important role in heat shock-induced activation of the MAPK and PI3-K pathways, was not observed in either WT or R-cells. These results suggest that neither IGF-IR nor EGFR contributes to the heat shock -induced activation of ERK and Akt in these cell lines.

Animals↗

PubMed2003

Roles of the insulin-like growth factor I receptor C-terminus in cellular radioresistance.

Available evidence suggests that insulin-like growth factor I receptor (IGF-IR) expression leads to increased cellular radioresistance. The most direct explanation of these findings predicts that IGF-IR is the source of survival signals in resistant cells. Mutational analysis revealed that protein truncated at amino acid 1245 in the C-terminus retained the ability of IGF-IR to confer radioresistance whereas point mutations at both Tyr-1250 and Tyr-1251 abrogated this effect using IGF-IR-deficient mouse embryo fibroblasts (R-) as a recipient. In cells expressing the latter mutant receptors, both phosphatidylinositol-3(') kinase (PI3-K) and mitogen-activated protein kinase (MAPK) signaling pathways remained intact, and addition of exogenous IGF-I could not change the radiosensitivity of these cells. Further analysis indicated that the abrogation of radioresistance required the presence of His-1293 and Lys-1294. These results suggest a novel regulatory role of the C-terminus of IGF-IR in mediating cellular radioresistance that may be independent of survival signals transmitted through this receptor.

Amino Acid Sequence↗

PubMed2003

Neck node metastasis after successful brachytherapy for early stage tongue carcinoma.

BACKGROUND AND PURPOSE: The accuracy of factors for predicting lymph node metastasis in patients with early-stage (stage I and II) mobile tongue carcinoma and prognostic factors associated with the clinical and pathological findings of lymph node metastasis were examined. MATERIAL AND METHODS: Between 1971 and 1998, 616 patients with early stage mobile tongue carcinoma were treated by brachytherapy with or without external irradiation. Neck lymph node metastasis occurred in a total of 237 cases, and 191 of them were not associated with primary failure. Neck dissection was performed in 169 of these 191 cases, and 16 cases were treated by radiotherapy. A pathological analysis was possible in 159 of the 169 neck dissection cases. RESULTS: There were 88 tongue cancer recurrences, and the incidence of neck metastasis was 38% (191/528) in the cases of primary controlled early tongue carcinoma, and 25% (38/151) and 41% (153/377), in stage-I and -II carcinoma, respectively. Neck metastasis was diagnosed within 12 months in 80% of cases, and within 24 months in 95%. Macroscopic appearance, tumor thickness and tumor length were identified as significant risk factors by a univariate analysis, but macroscopic appearance was the only significant risk factor identified by a multivariate analysis (P<0.001). The incidence of cervical lymph node metastasis was 62% among the invasive/ulcerative type tongue carcinomas, and was lower among the superficial type and exophytic/nodular type (20 and 35%, respectively). Regional and/or distant failure occurred in 75 of the 169 neck dissection cases (44%). The incidence of regional/distant failure was extremely high (49/68=72%) in the extra-nodal invasion group, and extra-nodal invasion was found even in small metastatic node less than 1 cm in length (20%). CONCLUSIONS: The macroscopic appearance of the primary tongue carcinoma has a major impact on the incidence of lymph node metastasis in patients with early tongue cancer, and extra-nodal invasion was the dominant risk factor for regional and distant failure. Treatment policy for clinically negative neck metastasis in early tongue cancer patients should be determined after considering the possibility of neck metastases and the morbidity associated with elective neck dissection.

Adult↗

PubMed2002

Redundancy of radioresistant signaling pathways originating from insulin-like growth factor I receptor.

The insulin-like growth factor I receptor (IGF-IR) has the ability to confer clonogenic radioresistance following ionizing irradiation. We attempted to determine the downstream pathways involved in IGF-IR-mediated radioresistance and used mouse embryo fibroblasts deficient in endogenous IGF-IR (R-) as recipients for a number of mutant IGF-IRs. Mutational analysis revealed that the tyrosine at residue 950 (Tyr-950) of IGF-IR, as well as the C-terminal domain, are required for radioresistance and that both domains must be mutated to abrogate the phenotype. Furthermore, the contribution of downstream pathways was analyzed by combining the use of wild-type or Tyr-950 and C-terminal mutants with specific inhibitors of phosphatidylinositol 3'-kinase (PI3-K) or mitogen-activated protein extracellular signal-regulated kinase (ERK) kinase (MEK). Radioresistance could be induced by IGF-IR as long as the ability of the receptor to stimulate the MEK/ERK pathway was retained. This was confirmed by the expression of constitutively active MEK in R- cells. The ability to stimulate the PI3-K pathway alone was not sufficient, but PI3-K activation coupled with MEK/ERK pathway-independent signals from the C terminus was able to induce radioresistance. Taken together, these results indicate that the IGF-IR-mediated radioresistant signaling mechanism progresses through redundant downstream pathways.

Animals↗

PubMed2002

Expression of cIAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy.

Inhibition of, or increased resistance to, apoptosis is a common property of cancer cells. This means that a constitutive activation of antiapoptotic molecules via genetic or epigenetic mechanisms, including gene amplification, may well be involved in carcinogenesis. Recently we reported that cIAP1, an inhibitor of apoptosis, is overexpressed through 11q22 amplification in cell lines derived from esophageal squamous cell carcinomas and is associated with resistance of esophageal squamous cell carcinomas to drug-induced apoptosis (I. Imoto et al. Cancer Res., 61: 6629-6634, 2001). Because amplification of 11q22 has been implicated in other malignancies also, including cervical squamous cell carcinomas (CSCCs), we attempted to correlate amplification and overexpression of cIAP1 with radiation sensitivity in CSCC-derived cell lines and primary CSCC tumors. In the nine cell lines we examined, two showed amplification and consistent overexpression of cIAP1, as well as significant resistance to radiation-induced cell death as compared with lines showing no cIAP1 amplification. Immunohistochemical analysis of 70 primary CSCCs from patients treated only with radiotherapy demonstrated that both overall survival and local recurrence-free survival was significantly poorer among patients with tumors showing high levels of nuclear cIAP1 staining than among patients whose tumors revealed little or no nuclear cIAP1. Multivariate analysis showed nuclear cIAP1 staining to be an independent predictive factor for local recurrence-free survival after radiotherapy among patients with CSCC. These findings demonstrate that cIAP1 may play an important role in the development/progression of this disease and that cIAP1 could be a novel predictive marker for resistance to radiotherapy in individual CSCC patients.

Adult↗

PubMed2002

Insulin-like growth factor I receptor is expressed at normal levels in Nijmegen breakage syndrome cells.

Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder sharing a pleiotropic phenotype with ataxia-telangiectasia (A-T), including increased radiosensitivity and cancer disposition. Insulin-like growth factor I receptor (IGF-IR) expression is reportedly decreased in A-T cells, which is thought to contribute to its increased radiosensitivity. In this study, we investigated whether the same mechanism underlies the radiosensitivity of NBS cells. GM7166VA7 cells lacking NBS1 protein displayed a phenotype of increased radiosensitivity, while the introduction of NBS1 cDNA conferred radioresistance comparable to normal cells. IGF-IR expression levels were essentially the same among normal, NBS, and NBS1-complemented NBS cells. There was no significant difference between NBS and NBS1-complemented cells in activation of major downstream pathways of IGF-IR upon IGF-I stimulation, including phosphatidylinositol-3(') kinase (PI3-K) and mitogen-activated protein kinase (MAPK). Collectively, IGF-IR-related events are unlikely to be disrupted in NBS cells, and therefore, defects in IGF-IR signaling do not explain the increased radiosensitivity of NBS cells.

Cell Line, Transformed↗

PubMed2002

Trimodal combination therapy for maxillary sinus carcinoma.

PURPOSE: This study was conducted to evaluate the effectiveness of trimodal combination therapy (radiotherapy, intra-arterial chemotherapy, antrotomy) for the treatment of primary maxillary sinus carcinoma. METHODS AND MATERIALS: Between 1977 and 1996, 110 patients with maxillary squamous cell carcinoma were treated with trimodal combination therapy at Tokyo Medical and Dental University Hospital. All tumors were classified according to the 1997 UICC TNM staging system. Eighty percent of patients had T3 or T4 tumors. The T3 and T4 tumors were also classified into three groups according to their location, as visualized using computed tomography: the posterior-lateral (P) group, the medial (M) group, and the upper (U) group. Eight patients received additional radiotherapy, and 37 patients underwent a second surgical procedure, in addition to the trimodal combination therapy. RESULTS: The 5-year cause-specific survival and local control rates were 71% and 65%, respectively. The 5-year local control rate was 80% for the T1+2 tumors, 64% for the T3 tumors, and 52% for the T4 tumors (p = 0.06). Patients in the P+M group who received a 5-fluorouracil (5-FU) dosage of more than 3500 mg had a better 5-year local control rate than patients who received a 5-FU dosage of less than 3500 mg (p = 0.01). No improvement in the local control rate after a second surgical procedure or additional irradiation treatment was observed in any of the groups. CONCLUSION: Trimodal combination therapy provides good local control, with the final outcome depending on the T stage of the tumor and the dosage of 5-FU.

Adult↗

PubMed2002

Site specific dependency of second primary cancer in early stage head and neck squamous cell carcinoma.

BACKGROUND: A study was conducted to determine the site specificity of second primary cancer (SPC) following early (Stage I and II) squamous cell carcinoma of the head and neck (SCH) and its impact on prognosis. METHODS: Between 1956 and 1999, 1,639 early stage SCHs in 1,609 patients were treated by radiotherapy at the authors' institution. The risk of additional respiratory and upper digestive tract (RUDT) carcinoma and the treatment outcome were reviewed for each SCH site. Second primary RUDT carcinomas were the second most common cause of death (113 cases) after death from primary SCH carcinomas (350 cases). RESULTS: Among the 1,609 early stage SCH patients, 333 second primary cancers were documented in 258 patients, 235 (71%) of which were RUDT carcinomas. The risk of SPCs was 3.2% per year, and the risk of SPCs in the RUDT region was 2.3% per year. The risk of SPCs was almost two times higher in males (3.7% per year) than in females (2.2% per year). The highest risk of SPC was observed in the oro-hypopharynx index cancer group (8.5% per year), and the lowest risks were observed in the epipharynx group (0% per year) and the maxillary sinus group (1.4% per year). CONCLUSIONS: Different SPC risks according to the SCH site result in a different prognosis for each site of early stage SCH. Long-term follow-up care after the initial treatment for early SCH should be continued according to the site of the initial SCH.

Adult↗

PubMed2002

The phosphatidylinositol-3 kinase pathway is not essential for insulin-like growth factor I receptor-mediated clonogenic radioresistance.

The insulin-like growth factor I receptor (IGF-IR) is known to induce clonogenic radioresistance in cells following ionizing irradiation. To explore the downstream signaling pathways, we focused on the phosphatidylinositol-3 kinase (PI3-K) pathway, which is thought to be the primary cell survival signal originating from the receptor. For this purpose, R- cells deficient in the endogenous IGF-IR were used as a recipient of the human IGF-IR with or without mutations at potential PI3-K activation sites: NPXY950 and Y1316XXM. Mutants with double mutation at Y950/Y1316 exhibited not abrogated, but reduced activation of IRS-1, PI3-K, and Akt upon IGF-I stimulation. However, the mutants had the same clonogenic radioresistance as cells with wild type (WT) receptors. Neither wortmannin nor LY294002, specific inhibitors of PI3-K, affected the radioresistance of cells with WT receptors at concentrations specific for PI3-K. Collectively, these results indicate that the PI3-K pathway is not essential for IGF-IR-mediated clonogenic radioresistance.

Animals↗

PubMed2002

[Relationship between apoptotic activity and radiosensitivity in solid tumors: does apoptosis always bring good clinical results?].

Apoptosis has recently been considered to be a predictor of tumor response or outcome following chemotherapy or radiotherapy. Although apoptosis clearly occurs in the very early stages following such treatments, it is unclear whether its frequency correlates with the likelihood of tumor cure following radiotherapy, especially in solid tumors, where the major mode of cell death is necrosis. This review discuses the relationship between apoptotic activity and radiosensitivity or tumor response from various points of view, including experimental systems and clinical conditions.

Animals↗