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Motoo Nagane, Yoshitaka Narita, Kazuhiko Mishima, Alexander Levitzki, Antony W. Burgess, Webster K. Cavenee and H. J. Su Huang

Object. Activation of signaling by the epidermal growth factor receptor (EGFR) through gene amplification or rearrangement is common in human malignancy, especially in a large fraction of de novo glioblastomas multiforme (GBMs). The most common mutant EGFR, (ΔEGFR, also known as de2–7 EGFR and EGFRvIII) lacks a portion of the extracellular domain, enhances tumorigenicity in vivo, and causes resistance to the chemotherapeutic drug cisplatin (CDDP). This resistance is due to the suppression of CDDP-induced apoptosis by the constitutively active tyrosine kinase activity of the receptor. The authors have investigated whether inhibition of AEGFR signaling by the tyrosine kinase inhibitor, tyrphostin AG1478, could sensitize tumor xenografts to CDDP and, thereby, enhance its therapeutic efficacy in animals.

Methods. Nude mice were inoculated either subcutaneously or intracerebrally with human GBM cells expressing ΔEGFR and were then systemically treated with CDDP and/or AG1478. Tumor volumes were monitored and tumor sections were analyzed by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assays or MIB-1 staining.

Expression of ΔEGFR, but not wild-type EGFR, conferred CDDP resistance to the cells in vivo. Inhibition of receptor signaling by the EGFR-specific tyrosine kinase inhibitor, AG1478, sensitized the xenografts to the cytotoxic effects of CDDP. This combined CDDP/AG1478 treatment significantly suppressed growth of subcutaneous xenografts in nude mice in a synergistic manner (p < 0.01 compared with vehicle control) without causing generalized toxicity, whereas treatments with CDDP or AG1478 alone were ineffective. The synergistic growth suppression by the CDDP/AG1478 combination was not observed in xenografts overexpressing wild-type EGFR or kinase-deficient ΔEGFR. The combined CDDP/AG1478 treatment induced tumor growth suppression, which correlated with increased apoptosis and reduced proliferation. This treatment also extended the life span of mice bearing intracerebral xenografts (p < 0.01 compared with controls).

Conclusions. The results of this study may provide the basis for the development of a novel and safe therapeutic strategy for the very aggressive ΔEGFR-expressing GBM.

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Satoshi Tanaka, Jiro Akimoto, Yoshitaka Narita, Hidehiro Oka and Takashi Tashiro

Object

Methylation of O6-methylguanine-DNA methyltransferase (MGMT) has been reported to be a good prognostic factor for patients with glioblastoma multiforme (GBM). To determine whether the absolute value of MGMT messenger RNA (mRNA) might be a prognostic factor and useful for predicting the therapeutic effectiveness of temozolomide, especially with regard to GBMs, the authors measured the absolute value of MGMT mRNA in gliomas by using real-time reverse-transcription polymerase chain reaction (RT-PCR).

Methods

MGMT mRNA was measured in 140 newly diagnosed gliomas by real-time RT-PCR using the Taq-Man probe. Among 73 GBMs, 45 had been initially treated with temozolomide and radiation.

Results

The mean MGMT mRNA value was significantly lower in oligodendroglial tumors than in other tumors. In the 73 GBMs, a significant prognostic factor for progression-free survival was fewer than 1000 copies/ μgRNA of MGMT mRNA (p = 0.0150). Of 45 patients with GBMs that had been treated with temozolomide and radiation, progression-free survival was significantly longer for those whose GMB had fewer than 1000 copies/μgRNA of MGMT mRNA than for those whose GBM had more than 1000 copies/μgRNA (p = 0.0090). In 32 patients with GBMs treated by temozolomide and radiation whose age was younger than 75 years and whose Karnofsky Performance Scale score was more than 70, progression-free and overall survival times were longer for those with GBMs of fewer than 5000 copies/μgRNA of MGMT mRNA than for those with GBMs of more than 5000 copies/μgRNA (p = 0.0365 and p = 0.0312).

Conclusions

MGMT mRNA might be useful as a prognostic factor and for predicting the results of therapy for GBMs treated by temozolomide. New individual adjuvant therapy based on the results of MGMT mRNA quantitation has been proposed.

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Hirokazu Takami, Avital Perry, Christopher S. Graffeo, Caterina Giannini, Yoshitaka Narita, Yoichi Nakazato, Nobuhito Saito, Ryo Nishikawa, Masao Matsutani, Koichi Ichimura and David J. Daniels

OBJECTIVE

Central nervous system (CNS) germ cell tumors (GCTs) are rare malignant neoplasms that arise predominantly in adolescents and young adults. CNS GCTs demonstrate characteristic trends in national associations, with implications for both tumor incidence and genetics. Although the incidence of CNS GCTs is markedly higher in East Asia than Western countries, direct comparative analyses between these CNS GCT populations are limited.

METHODS

In Japan, to facilitate the genomic analyses of CNS GCTs, the Intracranial Germ Cell Tumor Genome Analysis Consortium was established in 2011, and more than 200 cases of GCTs are available for both tumor tissue and clinical data, which is organized by the National Cancer Center (NCC) Japan. At the Mayo Clinic, there have been 98 cases of intracranial GCTs treated by the Department of Neurologic Surgery since 1988. In this paper, the authors compared the epidemiology, clinical presentation including location and histology, and prognosis between cases treated in the US and Japan.

RESULTS

There was no significant difference in age and sex distributions between the databases. However, there was a significant difference in the tumor locations; specifically, the frequency of basal ganglia was higher in the NCC database compared with the Mayo Clinic (8.4% vs 0%, p = 0.008), and bifocal location (neurohypophysis and pineal gland) was higher at the Mayo Clinic than at the NCC (18.8% vs 5.8%, p = 0.002). There was no difference in histological subdivisions between the databases. There was no difference in progression-free survival (PFS) and overall survival (OS) of germinoma cases and OS of nongerminomatous GCT (NGGCT) cases treated with chemotherapy and radiation therapy covering whole ventricles. However, PFS of NGGCTs differed significantly, and was better in the NCC cohorts (p = 0.04).

CONCLUSIONS

There appears to be a differential distribution of GCTs by neuroanatomical location between major geographic and national groups. Further study is warranted to better characterize any underlying genomic, epigenetic, or environmental factors that may be driving the phenotypic differences.